{"gene":"BTLA","run_date":"2026-06-09T22:02:45","timeline":{"discoveries":[{"year":2003,"finding":"BTLA is an immunoglobulin domain-containing glycoprotein with two immunoreceptor tyrosine-based inhibitory motifs (ITIMs). Crosslinking BTLA with antigen receptors induces its tyrosine phosphorylation and direct association with SHP-1 and SHP-2 phosphatases, attenuating IL-2 production. BTLA-deficient T cells show increased proliferation.","method":"Co-immunoprecipitation, phosphorylation assay, BTLA-deficient mouse phenotyping, cytokine production assay","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP with SHP-1/SHP-2, KO phenotype with defined cellular readout, replicated by multiple subsequent labs","pmids":["12796776"],"is_preprint":false},{"year":2005,"finding":"Crystal structure of the BTLA–HVEM complex at 2.8 Å resolution shows BTLA binds the N-terminal cysteine-rich domain 1 (CRD1) of HVEM using a unique binding surface distinct from other CD28-like receptors. BTLA adopts an immunoglobulin I-set fold. BTLA and HVEM form a 1:1 complex (confirmed by light scattering). Alanine-scanning mutagenesis of HVEM defined critical binding residues. BTLA recognizes the same surface on HVEM as herpes virus glycoprotein D (gD) using a similar binding motif.","method":"X-ray crystallography (2.8 Å), light scattering, alanine-scanning mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with mutagenesis validation, foundational structural paper","pmids":["16169851"],"is_preprint":false},{"year":2006,"finding":"BTLA cytoplasmic domain contains a third conserved tyrosine motif (beyond the two ITIMs) that recruits Grb-2 directly and the p85 subunit of PI3K indirectly (via Grb-2), as identified by phosphopeptide pulldown and mass spectrometry.","method":"Synthetic phosphopeptide pulldown, mass spectrometry, direct binding confirmation","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphopeptide pulldown with MS identification and direct binding confirmation, single lab","pmids":["16725108"],"is_preprint":false},{"year":2009,"finding":"BTLA and HVEM form a heterodimeric cis-complex on the surface of naive T cells. This cis-interaction inhibits HVEM-dependent NF-κB RelA activation by preventing oligomerization of HVEM and acting as a competitive inhibitor that blocks BTLA and CD160 from binding HVEM in trans, thereby maintaining T cells in a naive state.","method":"Co-immunoprecipitation, NF-κB reporter assay, genetic deletion of BTLA, pharmacologic disruption, surface expression analysis on human and mouse T cells","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, reporter assay, genetic and pharmacologic perturbation, orthogonal methods in one study","pmids":["19915044"],"is_preprint":false},{"year":2019,"finding":"Quantitative interactomics in primary effector T cells shows BTLA predominantly recruits SHP-1 and to a lesser extent SHP-2, whereas PD-1 predominantly recruits SHP-2. Both SHP-1 and SHP-2 complexes with PD-1 equally dampen TCR and CD28 signaling pathways.","method":"Quantitative mass spectrometry-based interactomics (SILAC), primary T cell biochemistry at the T cell–APC interface","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — quantitative MS interactomics in primary cells with multiple orthogonal validations, directly compared to PD-1 signalosome","pmids":["31189114"],"is_preprint":false},{"year":2020,"finding":"BTLA preferentially recruits SHP-1 over SHP-2 to more efficiently suppress T cell signaling compared to PD-1. In SHP1/SHP2 double-deficient primary T cells, BTLA (and PD-1) still potently inhibit cell proliferation and cytokine production, demonstrating a phosphatase-independent inhibitory mechanism, though more transiently than in wild-type cells.","method":"Reconstitution assays, primary T cell signaling assays, SHP1/SHP2 double-knockout T cells, proliferation and cytokine production readouts","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — clean double-KO primary T cells with defined signaling phenotype, multiple orthogonal readouts, single rigorous study","pmids":["32437509"],"is_preprint":false},{"year":2008,"finding":"HVEM and BTLA are required in dendritic cells and their surrounding microenvironment to maintain homeostatic control of CD8α- DC subsets in the spleen. HVEM- and BTLA-deficient DC subsets show a specific growth advantage in competitive bone marrow chimeric repopulation assays, establishing the HVEM-BTLA pathway as an inhibitory checkpoint for DC homeostasis that counterbalances LTβR-driven expansion.","method":"Competitive bone marrow chimeric mice, genetic deletion (HVEM-/-, BTLA-/- mice), spleen DC subset quantification","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — competitive chimera experiments with genetic KO, replicated across multiple mouse models in same study","pmids":["18097025"],"is_preprint":false},{"year":2008,"finding":"HVEM expression by radioresistant innate immune cells in the intestinal environment interacts with BTLA to prevent runaway intestinal inflammation; HVEM absence in Rag-/- recipients dramatically accelerates colitis in CD4+CD45RBhi T cell transfer model, while HVEM absence in donor T cells has only minor effect.","method":"Adoptive T cell transfer colitis model, HVEM-/- recipient vs donor analysis, Rag-/- bone marrow chimeras","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with clean KO, reciprocal donor/recipient experiments, defined inflammatory phenotype","pmids":["18519647"],"is_preprint":false},{"year":2011,"finding":"BTLA signaling into donor T cells (via its intracellular domain) inhibits antihost T cell responses and ameliorates GVHD. Separately, BTLA also serves as a ligand for HVEM, delivering prosurvival signals to donor T cells; a BTLA mutant lacking the intracellular signaling domain restored impaired survival of BTLA-deficient T cells, demonstrating ligand function independent of BTLA's receptor signaling.","method":"Agonistic anti-BTLA monoclonal antibody, BTLA signaling-domain deletion mutant, GVHD mouse model, survival and engraftment assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — domain-deletion mutagenesis in vivo, agonist antibody, genetic KO, multiple functional readouts","pmids":["21220749"],"is_preprint":false},{"year":2013,"finding":"BTLA transcription in γδ T cells is repressed by the transcription factor RORγt via its activating function-2 (AF-2) domain, while IL-7 increases BTLA surface levels. BTLA expression limits γδ T cell numbers and restricts IL-7-driven expansion of the CD27-RORγt+ population, and negatively regulates IL-17 and TNF production in CD27- γδ T cells.","method":"BTLA-deficient mice, RORγt AF-2 domain mutagenesis, IL-7 signaling assays, γδ T cell subset quantification, dermatitis disease model, cytokine production assays","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with defined subset phenotype, transcription factor domain mutagenesis, in vivo disease model with BTLA agonism rescue","pmids":["24315996"],"is_preprint":false},{"year":2013,"finding":"BTLA signaling into T cells through SHP-1 reduces TCR signaling and inhibits preformed CD40 ligand mobilization to the immunological synapse, thereby diminishing T cell help delivered to germinal center B cells. T cell-specific BTLA deficiency cooperates with B cell Bcl-2 overexpression to drive GC B cell outgrowth.","method":"BTLA conditional KO in T cells, HVEM KO in B cells, immunological synapse imaging, SHP-1 signaling assay, GC B cell quantification, lymphoma model","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO, synapse imaging, defined signaling mechanism via SHP-1, multiple orthogonal readouts","pmids":["31204070"],"is_preprint":false},{"year":2016,"finding":"BTLA expressed on DEC205+CD8+CD11c+ dendritic cells is required for efficient induction of extrathymic Foxp3+ regulatory T cells. Engagement of HVEM (receptor for BTLA) on T cells promotes Foxp3 expression through upregulation of CD5, which enables T cells to resist inhibition of Foxp3 expression by effector-differentiating cytokines.","method":"BTLA-deficient and HVEM-deficient mice, DC subset sorting, Treg induction assays, CD5 upregulation measurement, Foxp3 reporter","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO, DC subset-specific functional assays, defined molecular pathway (HVEM→CD5→Foxp3), multiple orthogonal methods","pmids":["27793593"],"is_preprint":false},{"year":2013,"finding":"BTLA expressed on CD8α+ dendritic cells functions as a trans-activating ligand that delivers positive co-signals through HVEM expressed on CD8+ T cells, promoting effector CD8 T cell survival and memory formation after vaccinia virus infection.","method":"Mixed adoptive transfer of HVEM-/- and BTLA-/- T cells, vaccinia virus infection model, effector survival and memory quantification","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mixed adoptive transfer epistasis, single lab, defined phenotype but indirect mechanistic inference","pmids":["24205056"],"is_preprint":false},{"year":2017,"finding":"The Grb-2 recruitment motif of BTLA mediates a costimulatory function in CD8+ T cells: BTLA mutants lacking the Grb-2 binding site show impaired IL-2 secretion and Src kinase activation following TCR stimulation, and CD8+BTLA+ TILs have improved survival and serial killing capacity compared to BTLA- counterparts.","method":"BTLA signaling domain mutants, reverse-phase protein array (RPPA), antigen-specific vaccination models with TCR-transgenic T cells, patient-derived xenograft model","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mutagenesis in functional assays, RPPA signaling analysis, in vivo models, single lab","pmids":["28754817"],"is_preprint":false},{"year":2015,"finding":"HVEM engagement of BTLA activates the Akt/PKB survival pathway in CD8+ TILs, protecting them from apoptosis while simultaneously inhibiting T cell division and cytokine production, demonstrating dual inhibitory and pro-survival signaling by BTLA.","method":"HVEM ligand stimulation assays, Akt/PKB phosphorylation assays, apoptosis assays, in vivo persistence tracking of TILs","journal":"Oncoimmunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct ligand stimulation with defined signaling pathway readout, single lab, functional consequences measured","pmids":["26405566"],"is_preprint":false},{"year":2024,"finding":"BTLA inhibits CAR T cells via recruitment of SHP-1 and SHP-2 upon trans engagement with HVEM expressed on regulatory T cells in the tumor microenvironment. BTLA knockout in CAR T cells improves tumor control and persistence in lymphoma and solid tumor models.","method":"BTLA knockout in CAR T cells (genetic deletion), co-culture with HVEM-expressing regulatory T cells, SHP-1/SHP-2 recruitment assays, in vivo lymphoma and solid tumor models","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with defined molecular mechanism (SHP-1/2 recruitment), multiple in vivo models, mechanistic follow-up","pmids":["38831106"],"is_preprint":false},{"year":2012,"finding":"BTLA expression in macrophages promotes macrophage viability and function, enhancing TNF-α and FGL2 production during viral hepatitis. In BTLA-/- mice, MHV-3-infected macrophages undergo rapid TRAIL-dependent apoptosis, reducing viral titres and liver damage.","method":"BTLA-/- mice, MHV-3 infection model, adoptive macrophage transfer, TRAIL blocking, BTLA antibody treatment, cytokine and liver enzyme measurement","journal":"Gut","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined cellular mechanism (TRAIL-dependent apoptosis), adoptive transfer rescue, single lab","pmids":["22637698"],"is_preprint":false},{"year":2012,"finding":"BTLA ligation in human B cells (activated via CpG/TLR9) selectively inhibits proliferation, cytokine production, and upregulation of co-stimulatory molecules upon engagement with HVEM, but does not inhibit chemokine secretion (IL-8 and MIP1β), demonstrating selective inhibitory function.","method":"BTLA/HVEM blocking antibodies, CpG-stimulated B cell functional assays, cytokine and chemokine measurement, B cell proliferation assay","journal":"Journal of molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor blocking with defined functional selectivity, human primary cells, single lab","pmids":["22903545"],"is_preprint":false},{"year":2022,"finding":"In the BTLA-HVEM cis-complex, BTLA-mediated inhibition is dominant and not impaired; co-expression of LIGHT or CD160 (but not BTLA) with HVEM induces strong constitutive HVEM signaling. The cis-BTLA-HVEM complex prevents HVEM costimulation by ligands on surrounding cells while retaining BTLA inhibitory signaling.","method":"T cell reporter systems, HVEM co-expression with various ligands, primary human T cell stimulation assays, HVEM antibody blocking","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assays plus primary T cell functional assays, single lab, multiple ligand comparisons","pmids":["36081508"],"is_preprint":false},{"year":2021,"finding":"Crystal structures of HVEM reveal distinct surfaces that engage LIGHT (TNF ligand) versus BTLA/CD160 (Ig superfamily ligands), including a human HVEM-LIGHT-CD160 ternary complex showing simultaneous binding. Mouse HVEM knockin mutants selectively recognizing either TNF or Ig ligands demonstrate that LIGHT drives bacterial clearance in the intestine while Ig ligands (BTLA/CD160) ameliorate liver inflammation.","method":"X-ray crystallography (ternary complex), HVEM knockin mutant mice, bacterial infection models, liver inflammation models","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus knockin mutagenesis in vivo with selective functional phenotypes, multiple independent models","pmids":["34709351"],"is_preprint":false},{"year":2011,"finding":"CD160 competes with BTLA for binding to HVEM at overlapping but slightly distinct sites on CRD1-3. CD160 binds HVEM with similar affinity to BTLA but with a slower dissociation rate. LIGHT does not affect HVEM binding to either CD160 or BTLA, confirming distinct binding surfaces.","method":"Surface plasmon resonance, N-terminal sequencing, mass spectrometry, HVEM mutagenesis, competitive binding assays","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — SPR kinetics, mutagenesis, competitive binding, multiple orthogonal biophysical methods","pmids":["21959263"],"is_preprint":false},{"year":2018,"finding":"BTLA function in lupus CD4+ T cells is impaired due to defective recruitment of BTLA to the immunological synapse following T cell stimulation, not reduced expression. Restoring intracellular lipid trafficking and normalizing lipid metabolism in lupus T cells corrects defective BTLA recruitment to the synapse and restores its inhibitory function.","method":"Immunological synapse imaging, BTLA localization assay, lipid metabolism rescue experiments, T cell activation inhibition assay, SLE patient primary cells","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct synapse localization imaging with functional consequence, rescue experiment, primary SLE patient cells, single lab","pmids":["29997289"],"is_preprint":false},{"year":2009,"finding":"In vivo administration of anti-BTLA monoclonal antibody induces profound and lasting downmodulation of BTLA expression on lymphoid and myeloid cells through receptor internalization.","method":"In vivo mAb administration, flow cytometry, receptor internalization assay","journal":"Immunobiology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single in vivo mAb study with surface expression readout only, limited mechanistic detail","pmids":["19837478"],"is_preprint":false},{"year":2024,"finding":"BTLA levels on CD4+ T cells are upregulated by IL-6 and TNF signaling pathways in HBV-ACLF. Antibody crosslinking of BTLA activates the PI3K-Akt pathway to inhibit CD4+ T cell activation, proliferation, and cytokine production while promoting apoptosis. BTLA knockdown promotes CD4+ T cell activation and proliferation. BTLA-/- ACLF mice show increased cytokine secretion and reduced mortality.","method":"BTLA crosslinking antibody assay, PI3K-Akt pathway analysis, BTLA knockdown (siRNA/shRNA), BTLA-/- mouse ACLF model, cytokine measurement","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse model, antibody crosslinking with defined signaling pathway, knockdown rescue, single lab","pmids":["38418488"],"is_preprint":false},{"year":2006,"finding":"Human BTLA is constitutively expressed on most CD4+ and CD8+ T cells and its expression progressively decreases upon T cell activation. Cross-linking BTLA with an agonistic monoclonal antibody inhibits T cell proliferation and production of IFN-γ and IL-10 in response to anti-CD3 stimulation, during both primary and secondary T cell responses.","method":"Anti-BTLA monoclonal antibody crosslinking, T cell proliferation assay, cytokine ELISA, flow cytometry","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — agonistic antibody crosslinking with functional readouts, replicated across multiple T cell response contexts","pmids":["16643847"],"is_preprint":false}],"current_model":"BTLA is an Ig superfamily co-inhibitory receptor that upon tyrosine phosphorylation recruits SHP-1 (predominantly) and SHP-2 via its ITIMs to suppress TCR and CD28 signaling; it also recruits Grb-2 and PI3K-p85 via a third cytoplasmic tyrosine motif to mediate a costimulatory/survival signal through Akt/PKB. Its sole ligand is HVEM (TNFRSF14), which it engages in a 1:1 complex at HVEM's CRD1 (structurally defined at 2.8 Å); BTLA and HVEM co-expressed on the same cell form an inhibitory cis-complex that blocks trans HVEM activation by other ligands (LIGHT, CD160) while preserving BTLA's inhibitory signaling. When presented in trans by dendritic cells, BTLA acts as an activating ligand for HVEM on T cells to promote CD8+ memory formation and Foxp3+ Treg induction via CD5 upregulation. BTLA signals through SHP-1 to reduce preformed CD40L mobilization at the immunological synapse and dampen T cell help to germinal center B cells; SHP-1/2-independent inhibitory mechanisms also exist. Defective BTLA function in SLE T cells results from impaired recruitment to the immunological synapse due to altered lipid metabolism, which can be pharmacologically corrected."},"narrative":{"mechanistic_narrative":"BTLA is an immunoglobulin-superfamily co-inhibitory receptor that restrains adaptive and innate immune activation by dampening antigen-receptor signaling in T and B cells [PMID:12796776, PMID:16643847]. Following crosslinking with antigen receptors, BTLA becomes tyrosine-phosphorylated on its two ITIMs and recruits the phosphatases SHP-1 and SHP-2, attenuating IL-2 production and limiting T cell proliferation [PMID:12796776]; quantitative interactomics in primary T cells establishes that BTLA preferentially recruits SHP-1, distinguishing its signalosome from the SHP-2-biased PD-1, while a phosphatase-independent inhibitory mechanism also operates [PMID:31189114, PMID:32437509]. A third cytoplasmic tyrosine motif recruits Grb-2 and, indirectly, the PI3K p85 subunit, mediating a costimulatory/pro-survival arm that drives Akt signaling, IL-2 secretion and TIL persistence [PMID:16725108, PMID:28754817, PMID:26405566]. BTLA engages a single ligand, HVEM (TNFRSF14), forming a 1:1 complex at HVEM's N-terminal CRD1 through a binding surface shared with herpesvirus glycoprotein D and distinct from the LIGHT-binding surface [PMID:16169851, PMID:34709351, PMID:21959263]. When co-expressed with HVEM on the same cell, BTLA forms an inhibitory cis-heterodimer that blocks HVEM oligomerization and trans engagement by LIGHT or CD160 while retaining its own inhibitory signaling, holding T cells in a naive state [PMID:19915044, PMID:36081508]. Presented in trans, BTLA also acts as an activating ligand for HVEM on T cells, delivering pro-survival signals that promote CD8+ effector/memory formation and extrathymic Foxp3+ Treg induction via CD5 upregulation [PMID:21220749, PMID:27793593, PMID:24205056]. Physiologically, the BTLA-HVEM axis is an inhibitory checkpoint for dendritic-cell homeostasis, intestinal and hepatic inflammation, germinal-center T cell help, and γδ T cell expansion [PMID:18097025, PMID:18519647, PMID:24315996, PMID:31204070], and BTLA-mediated SHP-1/SHP-2 recruitment upon trans engagement with HVEM on regulatory T cells suppresses CAR T cells in tumors [PMID:38831106].","teleology":[{"year":2003,"claim":"Established BTLA as a bona fide inhibitory receptor by linking its ITIMs to phosphatase recruitment and a defined proliferative phenotype, answering whether BTLA actively transduces a suppressive signal.","evidence":"Co-IP of SHP-1/SHP-2, phosphorylation assays, and BTLA-deficient T cell phenotyping","pmids":["12796776"],"confidence":"High","gaps":["Did not resolve relative contribution of SHP-1 vs SHP-2","Did not identify the ligand or costimulatory motif"]},{"year":2005,"claim":"Defined the structural basis of BTLA-HVEM recognition, answering how an Ig-fold receptor engages a TNFR-family ligand and showing the binding surface overlaps with viral gD.","evidence":"X-ray crystallography at 2.8 Å with light scattering and alanine-scanning mutagenesis","pmids":["16169851"],"confidence":"High","gaps":["Did not address cis vs trans geometry on cells","Did not compare to CD160 or LIGHT binding sites"]},{"year":2006,"claim":"Identified a costimulatory arm of BTLA by mapping a third tyrosine motif recruiting Grb-2 and PI3K p85, revealing BTLA is not purely inhibitory.","evidence":"Synthetic phosphopeptide pulldown with mass spectrometry and direct binding confirmation","pmids":["16725108"],"confidence":"Medium","gaps":["Single lab, in vitro phosphopeptide system","Functional consequence of Grb-2/PI3K recruitment not tested here"]},{"year":2008,"claim":"Placed the BTLA-HVEM axis as an inhibitory checkpoint controlling dendritic-cell homeostasis and intestinal inflammation, extending its role beyond T cell-intrinsic signaling.","evidence":"Competitive bone marrow chimeras and adoptive T cell transfer colitis models with HVEM/BTLA KO mice","pmids":["18097025","18519647"],"confidence":"High","gaps":["Cellular source of HVEM and directionality of signaling not fully resolved","Molecular mechanism downstream not defined"]},{"year":2009,"claim":"Defined the cis-heterodimer mechanism, answering how BTLA-HVEM co-expression maintains naive T cells by competitively blocking trans HVEM activation.","evidence":"Reciprocal Co-IP, NF-κB reporter assays, genetic and pharmacologic disruption on human and mouse T cells","pmids":["19915044"],"confidence":"High","gaps":["Stoichiometry of the cis-complex on the cell surface not quantified","Did not resolve whether inhibitory signaling persists in cis"]},{"year":2011,"claim":"Demonstrated BTLA functions bidirectionally as both a receptor and an HVEM ligand, with the ligand role delivering pro-survival signals independent of BTLA's own cytoplasmic signaling.","evidence":"Agonistic anti-BTLA antibody, signaling-domain deletion mutant, and GVHD mouse model; SPR/competition mapping of CD160 vs BTLA on HVEM","pmids":["21220749","21959263"],"confidence":"High","gaps":["Physiological settings favoring ligand vs receptor function not delineated","Threshold for trans vs cis engagement unclear"]},{"year":2013,"claim":"Expanded BTLA's regulatory reach to γδ T cells and identified RORγt-mediated transcriptional control, and showed DC-expressed BTLA acts as a trans-activating ligand promoting CD8 memory.","evidence":"BTLA KO mice, RORγt AF-2 domain mutagenesis, IL-7 assays, and mixed adoptive transfer with vaccinia infection","pmids":["24315996","24205056"],"confidence":"Medium","gaps":["Memory-promoting trans-ligand mechanism is inferred indirectly","Coupling of transcriptional regulation to surface function incompletely defined"]},{"year":2015,"claim":"Resolved that BTLA delivers dual outputs in CD8+ TILs—inhibiting division/cytokines while activating Akt-driven survival—through engagement by HVEM.","evidence":"HVEM ligand stimulation, Akt phosphorylation and apoptosis assays, in vivo TIL persistence tracking","pmids":["26405566"],"confidence":"Medium","gaps":["Single lab","Did not map which cytoplasmic motif drives the Akt survival arm in this context"]},{"year":2016,"claim":"Connected the BTLA-HVEM axis to peripheral tolerance by showing DC-expressed BTLA induces Foxp3+ Tregs via an HVEM→CD5→Foxp3 pathway in T cells.","evidence":"BTLA and HVEM KO mice, DC subset sorting, Treg induction and CD5/Foxp3 reporter assays","pmids":["27793593"],"confidence":"High","gaps":["Biochemical link between HVEM engagement and CD5 upregulation not defined","Relative contribution to peripheral tolerance in vivo not quantified"]},{"year":2017,"claim":"Functionally validated the Grb-2 motif as a costimulatory determinant in CD8+ T cells, tying the 2006 biochemistry to IL-2 output, Src activation, and TIL fitness.","evidence":"BTLA signaling-domain mutants, RPPA signaling analysis, and TCR-transgenic vaccination plus PDX models","pmids":["28754817"],"confidence":"Medium","gaps":["Single lab","Balance between Grb-2 costimulation and ITIM inhibition context-dependence unresolved"]},{"year":2018,"claim":"Showed that BTLA dysfunction in lupus arises from failed recruitment to the immunological synapse rather than loss of expression, identifying lipid metabolism as a correctable upstream defect.","evidence":"Synapse imaging, BTLA localization assays, and lipid-metabolism rescue in SLE patient primary CD4+ T cells","pmids":["29997289"],"confidence":"Medium","gaps":["Single lab","Molecular link between lipid trafficking and BTLA synapse targeting not defined"]},{"year":2019,"claim":"Quantified the BTLA signalosome relative to PD-1, establishing SHP-1 dominance for BTLA versus SHP-2 dominance for PD-1 in primary effector T cells.","evidence":"SILAC quantitative interactomics at the T cell–APC interface in primary cells","pmids":["31189114"],"confidence":"High","gaps":["Did not test whether SHP-1 bias is required for differential potency in vivo"]},{"year":2019,"claim":"Defined a tissue-level inhibitory mechanism whereby BTLA-SHP-1 signaling limits CD40L mobilization at the synapse to restrain germinal-center T cell help.","evidence":"T cell conditional BTLA KO, B cell HVEM KO, synapse imaging, SHP-1 assays and a lymphoma model","pmids":["31204070"],"confidence":"High","gaps":["Mechanism coupling SHP-1 to CD40L vesicle mobilization not biochemically resolved"]},{"year":2020,"claim":"Demonstrated that BTLA retains potent inhibitory function in SHP1/SHP2 double-deficient T cells, establishing a phosphatase-independent suppressive mechanism.","evidence":"Reconstitution and SHP1/SHP2 double-knockout primary T cell signaling assays with proliferation/cytokine readouts","pmids":["32437509"],"confidence":"High","gaps":["Identity of the phosphatase-independent effector not determined","Why inhibition is more transient without SHP1/2 unexplained"]},{"year":2021,"claim":"Structurally and genetically separated HVEM's TNF-ligand and Ig-ligand engagement surfaces, linking BTLA/CD160 to control of liver inflammation versus LIGHT-driven bacterial clearance.","evidence":"Ternary HVEM-LIGHT-CD160 crystal structure and HVEM knockin mutant mice in infection and inflammation models","pmids":["34709351"],"confidence":"High","gaps":["Did not isolate BTLA-specific from CD160-specific contributions in vivo"]},{"year":2022,"claim":"Clarified that within the cis-complex BTLA inhibition is dominant and preserved, while only LIGHT or CD160 (not BTLA) drive constitutive HVEM costimulation.","evidence":"T cell reporter systems with HVEM/ligand co-expression and primary human T cell stimulation assays","pmids":["36081508"],"confidence":"Medium","gaps":["Single lab","Quantitative surface stoichiometry of cis-complex not measured"]},{"year":2024,"claim":"Translated BTLA inhibition to engineered immunity, showing trans HVEM on Tregs recruits SHP-1/SHP-2 to BTLA on CAR T cells, and that BTLA knockout improves anti-tumor control.","evidence":"BTLA knockout CAR T cells, co-culture with HVEM+ Tregs, SHP recruitment assays, and in vivo lymphoma/solid tumor models","pmids":["38831106"],"confidence":"High","gaps":["Did not address the phosphatase-independent inhibitory arm in CAR T cells"]},{"year":null,"claim":"The molecular identity of BTLA's phosphatase-independent inhibitory effector and the rules governing the switch between its inhibitory receptor, costimulatory Grb-2/PI3K, and HVEM-ligand functions in vivo remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No effector identified for SHP-independent inhibition","No unified model predicting cis-inhibition vs trans-ligand vs costimulatory outputs"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,24]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,4,5]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[8,11,12]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,4,13]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,3,24]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,6,7,11]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,3,14]}],"complexes":["BTLA-HVEM cis-heterodimer","BTLA-SHP-1/SHP-2 signalosome"],"partners":["HVEM","SHP-1","SHP-2","GRB2","PIK3R1","CD160"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q7Z6A9","full_name":"B- and T-lymphocyte attenuator","aliases":["B- and T-lymphocyte-associated protein"],"length_aa":289,"mass_kda":32.8,"function":"Inhibitory receptor on lymphocytes that negatively regulates antigen receptor signaling via PTPN6/SHP-1 and PTPN11/SHP-2 (PubMed:12796776, PubMed:14652006, PubMed:15568026, PubMed:18193050). May interact in cis (on the same cell) or in trans (on other cells) with TNFRSF14 (PubMed:19915044). In cis interactions, appears to play an immune regulatory role inhibiting in trans interactions in naive T cells to maintain a resting state. 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of renal cell carcinoma in the Polish population.","date":"2016","source":"Urologic oncology","url":"https://pubmed.ncbi.nlm.nih.gov/27234378","citation_count":21,"is_preprint":false},{"pmid":"27743606","id":"PMC_27743606","title":"Hepatic expansion of virus-specific CD8+BTLA+ T cells with regulatory properties in chronic hepatitis B virus infection.","date":"2016","source":"Cellular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/27743606","citation_count":21,"is_preprint":false},{"pmid":"27933341","id":"PMC_27933341","title":"Intragenic Variations in BTLA Gene Influence mRNA Expression of BTLA Gene in Chronic Lymphocytic Leukemia Patients and Confer Susceptibility to Chronic Lymphocytic Leukemia.","date":"2016","source":"Archivum immunologiae et therapiae experimentalis","url":"https://pubmed.ncbi.nlm.nih.gov/27933341","citation_count":20,"is_preprint":false},{"pmid":"23067542","id":"PMC_23067542","title":"The intrahepatic expression and distribution of BTLA and its ligand HVEM in patients with HBV-related acute-on-chronic liver failure.","date":"2012","source":"Diagnostic pathology","url":"https://pubmed.ncbi.nlm.nih.gov/23067542","citation_count":20,"is_preprint":false},{"pmid":"27717503","id":"PMC_27717503","title":"BTLA-expressing CD11c antigen presenting cells in patients with active tuberculosis exhibit low capacity to stimulate T cell proliferation.","date":"2016","source":"Cellular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/27717503","citation_count":20,"is_preprint":false},{"pmid":"22179929","id":"PMC_22179929","title":"The expression and anatomical distribution of BTLA and its ligand HVEM in rheumatoid synovium.","date":"2012","source":"Inflammation","url":"https://pubmed.ncbi.nlm.nih.gov/22179929","citation_count":19,"is_preprint":false},{"pmid":"33238640","id":"PMC_33238640","title":"Fragments of gD Protein as Inhibitors of BTLA/HVEM Complex Formation-Design, Synthesis, and Cellular Studies.","date":"2020","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33238640","citation_count":19,"is_preprint":false},{"pmid":"33332777","id":"PMC_33332777","title":"The BTLA and PD-1 signaling pathways independently regulate the proliferation and cytotoxicity of human peripheral blood γδ T cells.","date":"2020","source":"Immunity, inflammation and disease","url":"https://pubmed.ncbi.nlm.nih.gov/33332777","citation_count":19,"is_preprint":false},{"pmid":"16426492","id":"PMC_16426492","title":"BTLA, a new inhibitory B7 family receptor with a TNFR family ligand.","date":"2005","source":"Cellular & molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/16426492","citation_count":19,"is_preprint":false},{"pmid":"33968071","id":"PMC_33968071","title":"BTLA Expression and Function Are Impaired on SLE B Cells.","date":"2021","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33968071","citation_count":18,"is_preprint":false},{"pmid":"32060969","id":"PMC_32060969","title":"Association between BTLA polymorphisms and susceptibility to esophageal squamous cell carcinoma in the Chinese population.","date":"2020","source":"Journal of clinical laboratory analysis","url":"https://pubmed.ncbi.nlm.nih.gov/32060969","citation_count":18,"is_preprint":false},{"pmid":"24321139","id":"PMC_24321139","title":"BTLA as a biomarker and mediator of sepsis-induced immunosuppression.","date":"2013","source":"Critical care (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/24321139","citation_count":18,"is_preprint":false},{"pmid":"33732243","id":"PMC_33732243","title":"Combined Immunotherapy With Belatacept and BTLA Overexpression Attenuates Acute Rejection Following Kidney Transplantation.","date":"2021","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33732243","citation_count":18,"is_preprint":false},{"pmid":"28393074","id":"PMC_28393074","title":"Adenovirus-Mediated CCR7 and BTLA Overexpression Enhances Immune Tolerance and Migration in Immature Dendritic Cells.","date":"2017","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/28393074","citation_count":18,"is_preprint":false},{"pmid":"27851922","id":"PMC_27851922","title":"BTLA+ Dendritic Cells: The Regulatory T Cell Force Awakens.","date":"2016","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/27851922","citation_count":18,"is_preprint":false},{"pmid":"26277622","id":"PMC_26277622","title":"BTLA expression declines on B cells of the aged and is associated with low responsiveness to the trivalent influenza vaccine.","date":"2015","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/26277622","citation_count":17,"is_preprint":false},{"pmid":"27194787","id":"PMC_27194787","title":"Regulatory T Cell Dysfunction Acquiesces to BTLA+ Regulatory B Cells Subsequent to Oral Intervention in Experimental Autoimmune Encephalomyelitis.","date":"2016","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/27194787","citation_count":17,"is_preprint":false},{"pmid":"19702559","id":"PMC_19702559","title":"Modulation of T cell proliferation through the LIGHT-HVEM-BTLA cosignaling pathway.","date":"2009","source":"Recent patents on DNA & gene sequences","url":"https://pubmed.ncbi.nlm.nih.gov/19702559","citation_count":16,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":47824,"output_tokens":6189,"usd":0.118153,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15206,"output_tokens":5200,"usd":0.103015,"stage2_stop_reason":"end_turn"},"total_usd":0.221168,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"BTLA is an immunoglobulin domain-containing glycoprotein with two immunoreceptor tyrosine-based inhibitory motifs (ITIMs). Crosslinking BTLA with antigen receptors induces its tyrosine phosphorylation and direct association with SHP-1 and SHP-2 phosphatases, attenuating IL-2 production. BTLA-deficient T cells show increased proliferation.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation assay, BTLA-deficient mouse phenotyping, cytokine production assay\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP with SHP-1/SHP-2, KO phenotype with defined cellular readout, replicated by multiple subsequent labs\",\n      \"pmids\": [\"12796776\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Crystal structure of the BTLA–HVEM complex at 2.8 Å resolution shows BTLA binds the N-terminal cysteine-rich domain 1 (CRD1) of HVEM using a unique binding surface distinct from other CD28-like receptors. BTLA adopts an immunoglobulin I-set fold. BTLA and HVEM form a 1:1 complex (confirmed by light scattering). Alanine-scanning mutagenesis of HVEM defined critical binding residues. BTLA recognizes the same surface on HVEM as herpes virus glycoprotein D (gD) using a similar binding motif.\",\n      \"method\": \"X-ray crystallography (2.8 Å), light scattering, alanine-scanning mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with mutagenesis validation, foundational structural paper\",\n      \"pmids\": [\"16169851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"BTLA cytoplasmic domain contains a third conserved tyrosine motif (beyond the two ITIMs) that recruits Grb-2 directly and the p85 subunit of PI3K indirectly (via Grb-2), as identified by phosphopeptide pulldown and mass spectrometry.\",\n      \"method\": \"Synthetic phosphopeptide pulldown, mass spectrometry, direct binding confirmation\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphopeptide pulldown with MS identification and direct binding confirmation, single lab\",\n      \"pmids\": [\"16725108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"BTLA and HVEM form a heterodimeric cis-complex on the surface of naive T cells. This cis-interaction inhibits HVEM-dependent NF-κB RelA activation by preventing oligomerization of HVEM and acting as a competitive inhibitor that blocks BTLA and CD160 from binding HVEM in trans, thereby maintaining T cells in a naive state.\",\n      \"method\": \"Co-immunoprecipitation, NF-κB reporter assay, genetic deletion of BTLA, pharmacologic disruption, surface expression analysis on human and mouse T cells\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, reporter assay, genetic and pharmacologic perturbation, orthogonal methods in one study\",\n      \"pmids\": [\"19915044\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Quantitative interactomics in primary effector T cells shows BTLA predominantly recruits SHP-1 and to a lesser extent SHP-2, whereas PD-1 predominantly recruits SHP-2. Both SHP-1 and SHP-2 complexes with PD-1 equally dampen TCR and CD28 signaling pathways.\",\n      \"method\": \"Quantitative mass spectrometry-based interactomics (SILAC), primary T cell biochemistry at the T cell–APC interface\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — quantitative MS interactomics in primary cells with multiple orthogonal validations, directly compared to PD-1 signalosome\",\n      \"pmids\": [\"31189114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"BTLA preferentially recruits SHP-1 over SHP-2 to more efficiently suppress T cell signaling compared to PD-1. In SHP1/SHP2 double-deficient primary T cells, BTLA (and PD-1) still potently inhibit cell proliferation and cytokine production, demonstrating a phosphatase-independent inhibitory mechanism, though more transiently than in wild-type cells.\",\n      \"method\": \"Reconstitution assays, primary T cell signaling assays, SHP1/SHP2 double-knockout T cells, proliferation and cytokine production readouts\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — clean double-KO primary T cells with defined signaling phenotype, multiple orthogonal readouts, single rigorous study\",\n      \"pmids\": [\"32437509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"HVEM and BTLA are required in dendritic cells and their surrounding microenvironment to maintain homeostatic control of CD8α- DC subsets in the spleen. HVEM- and BTLA-deficient DC subsets show a specific growth advantage in competitive bone marrow chimeric repopulation assays, establishing the HVEM-BTLA pathway as an inhibitory checkpoint for DC homeostasis that counterbalances LTβR-driven expansion.\",\n      \"method\": \"Competitive bone marrow chimeric mice, genetic deletion (HVEM-/-, BTLA-/- mice), spleen DC subset quantification\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — competitive chimera experiments with genetic KO, replicated across multiple mouse models in same study\",\n      \"pmids\": [\"18097025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"HVEM expression by radioresistant innate immune cells in the intestinal environment interacts with BTLA to prevent runaway intestinal inflammation; HVEM absence in Rag-/- recipients dramatically accelerates colitis in CD4+CD45RBhi T cell transfer model, while HVEM absence in donor T cells has only minor effect.\",\n      \"method\": \"Adoptive T cell transfer colitis model, HVEM-/- recipient vs donor analysis, Rag-/- bone marrow chimeras\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with clean KO, reciprocal donor/recipient experiments, defined inflammatory phenotype\",\n      \"pmids\": [\"18519647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"BTLA signaling into donor T cells (via its intracellular domain) inhibits antihost T cell responses and ameliorates GVHD. Separately, BTLA also serves as a ligand for HVEM, delivering prosurvival signals to donor T cells; a BTLA mutant lacking the intracellular signaling domain restored impaired survival of BTLA-deficient T cells, demonstrating ligand function independent of BTLA's receptor signaling.\",\n      \"method\": \"Agonistic anti-BTLA monoclonal antibody, BTLA signaling-domain deletion mutant, GVHD mouse model, survival and engraftment assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — domain-deletion mutagenesis in vivo, agonist antibody, genetic KO, multiple functional readouts\",\n      \"pmids\": [\"21220749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"BTLA transcription in γδ T cells is repressed by the transcription factor RORγt via its activating function-2 (AF-2) domain, while IL-7 increases BTLA surface levels. BTLA expression limits γδ T cell numbers and restricts IL-7-driven expansion of the CD27-RORγt+ population, and negatively regulates IL-17 and TNF production in CD27- γδ T cells.\",\n      \"method\": \"BTLA-deficient mice, RORγt AF-2 domain mutagenesis, IL-7 signaling assays, γδ T cell subset quantification, dermatitis disease model, cytokine production assays\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with defined subset phenotype, transcription factor domain mutagenesis, in vivo disease model with BTLA agonism rescue\",\n      \"pmids\": [\"24315996\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"BTLA signaling into T cells through SHP-1 reduces TCR signaling and inhibits preformed CD40 ligand mobilization to the immunological synapse, thereby diminishing T cell help delivered to germinal center B cells. T cell-specific BTLA deficiency cooperates with B cell Bcl-2 overexpression to drive GC B cell outgrowth.\",\n      \"method\": \"BTLA conditional KO in T cells, HVEM KO in B cells, immunological synapse imaging, SHP-1 signaling assay, GC B cell quantification, lymphoma model\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO, synapse imaging, defined signaling mechanism via SHP-1, multiple orthogonal readouts\",\n      \"pmids\": [\"31204070\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"BTLA expressed on DEC205+CD8+CD11c+ dendritic cells is required for efficient induction of extrathymic Foxp3+ regulatory T cells. Engagement of HVEM (receptor for BTLA) on T cells promotes Foxp3 expression through upregulation of CD5, which enables T cells to resist inhibition of Foxp3 expression by effector-differentiating cytokines.\",\n      \"method\": \"BTLA-deficient and HVEM-deficient mice, DC subset sorting, Treg induction assays, CD5 upregulation measurement, Foxp3 reporter\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO, DC subset-specific functional assays, defined molecular pathway (HVEM→CD5→Foxp3), multiple orthogonal methods\",\n      \"pmids\": [\"27793593\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"BTLA expressed on CD8α+ dendritic cells functions as a trans-activating ligand that delivers positive co-signals through HVEM expressed on CD8+ T cells, promoting effector CD8 T cell survival and memory formation after vaccinia virus infection.\",\n      \"method\": \"Mixed adoptive transfer of HVEM-/- and BTLA-/- T cells, vaccinia virus infection model, effector survival and memory quantification\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mixed adoptive transfer epistasis, single lab, defined phenotype but indirect mechanistic inference\",\n      \"pmids\": [\"24205056\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The Grb-2 recruitment motif of BTLA mediates a costimulatory function in CD8+ T cells: BTLA mutants lacking the Grb-2 binding site show impaired IL-2 secretion and Src kinase activation following TCR stimulation, and CD8+BTLA+ TILs have improved survival and serial killing capacity compared to BTLA- counterparts.\",\n      \"method\": \"BTLA signaling domain mutants, reverse-phase protein array (RPPA), antigen-specific vaccination models with TCR-transgenic T cells, patient-derived xenograft model\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mutagenesis in functional assays, RPPA signaling analysis, in vivo models, single lab\",\n      \"pmids\": [\"28754817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"HVEM engagement of BTLA activates the Akt/PKB survival pathway in CD8+ TILs, protecting them from apoptosis while simultaneously inhibiting T cell division and cytokine production, demonstrating dual inhibitory and pro-survival signaling by BTLA.\",\n      \"method\": \"HVEM ligand stimulation assays, Akt/PKB phosphorylation assays, apoptosis assays, in vivo persistence tracking of TILs\",\n      \"journal\": \"Oncoimmunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct ligand stimulation with defined signaling pathway readout, single lab, functional consequences measured\",\n      \"pmids\": [\"26405566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"BTLA inhibits CAR T cells via recruitment of SHP-1 and SHP-2 upon trans engagement with HVEM expressed on regulatory T cells in the tumor microenvironment. BTLA knockout in CAR T cells improves tumor control and persistence in lymphoma and solid tumor models.\",\n      \"method\": \"BTLA knockout in CAR T cells (genetic deletion), co-culture with HVEM-expressing regulatory T cells, SHP-1/SHP-2 recruitment assays, in vivo lymphoma and solid tumor models\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with defined molecular mechanism (SHP-1/2 recruitment), multiple in vivo models, mechanistic follow-up\",\n      \"pmids\": [\"38831106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"BTLA expression in macrophages promotes macrophage viability and function, enhancing TNF-α and FGL2 production during viral hepatitis. In BTLA-/- mice, MHV-3-infected macrophages undergo rapid TRAIL-dependent apoptosis, reducing viral titres and liver damage.\",\n      \"method\": \"BTLA-/- mice, MHV-3 infection model, adoptive macrophage transfer, TRAIL blocking, BTLA antibody treatment, cytokine and liver enzyme measurement\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined cellular mechanism (TRAIL-dependent apoptosis), adoptive transfer rescue, single lab\",\n      \"pmids\": [\"22637698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"BTLA ligation in human B cells (activated via CpG/TLR9) selectively inhibits proliferation, cytokine production, and upregulation of co-stimulatory molecules upon engagement with HVEM, but does not inhibit chemokine secretion (IL-8 and MIP1β), demonstrating selective inhibitory function.\",\n      \"method\": \"BTLA/HVEM blocking antibodies, CpG-stimulated B cell functional assays, cytokine and chemokine measurement, B cell proliferation assay\",\n      \"journal\": \"Journal of molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor blocking with defined functional selectivity, human primary cells, single lab\",\n      \"pmids\": [\"22903545\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In the BTLA-HVEM cis-complex, BTLA-mediated inhibition is dominant and not impaired; co-expression of LIGHT or CD160 (but not BTLA) with HVEM induces strong constitutive HVEM signaling. The cis-BTLA-HVEM complex prevents HVEM costimulation by ligands on surrounding cells while retaining BTLA inhibitory signaling.\",\n      \"method\": \"T cell reporter systems, HVEM co-expression with various ligands, primary human T cell stimulation assays, HVEM antibody blocking\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assays plus primary T cell functional assays, single lab, multiple ligand comparisons\",\n      \"pmids\": [\"36081508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Crystal structures of HVEM reveal distinct surfaces that engage LIGHT (TNF ligand) versus BTLA/CD160 (Ig superfamily ligands), including a human HVEM-LIGHT-CD160 ternary complex showing simultaneous binding. Mouse HVEM knockin mutants selectively recognizing either TNF or Ig ligands demonstrate that LIGHT drives bacterial clearance in the intestine while Ig ligands (BTLA/CD160) ameliorate liver inflammation.\",\n      \"method\": \"X-ray crystallography (ternary complex), HVEM knockin mutant mice, bacterial infection models, liver inflammation models\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus knockin mutagenesis in vivo with selective functional phenotypes, multiple independent models\",\n      \"pmids\": [\"34709351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CD160 competes with BTLA for binding to HVEM at overlapping but slightly distinct sites on CRD1-3. CD160 binds HVEM with similar affinity to BTLA but with a slower dissociation rate. LIGHT does not affect HVEM binding to either CD160 or BTLA, confirming distinct binding surfaces.\",\n      \"method\": \"Surface plasmon resonance, N-terminal sequencing, mass spectrometry, HVEM mutagenesis, competitive binding assays\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — SPR kinetics, mutagenesis, competitive binding, multiple orthogonal biophysical methods\",\n      \"pmids\": [\"21959263\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"BTLA function in lupus CD4+ T cells is impaired due to defective recruitment of BTLA to the immunological synapse following T cell stimulation, not reduced expression. Restoring intracellular lipid trafficking and normalizing lipid metabolism in lupus T cells corrects defective BTLA recruitment to the synapse and restores its inhibitory function.\",\n      \"method\": \"Immunological synapse imaging, BTLA localization assay, lipid metabolism rescue experiments, T cell activation inhibition assay, SLE patient primary cells\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct synapse localization imaging with functional consequence, rescue experiment, primary SLE patient cells, single lab\",\n      \"pmids\": [\"29997289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"In vivo administration of anti-BTLA monoclonal antibody induces profound and lasting downmodulation of BTLA expression on lymphoid and myeloid cells through receptor internalization.\",\n      \"method\": \"In vivo mAb administration, flow cytometry, receptor internalization assay\",\n      \"journal\": \"Immunobiology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single in vivo mAb study with surface expression readout only, limited mechanistic detail\",\n      \"pmids\": [\"19837478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"BTLA levels on CD4+ T cells are upregulated by IL-6 and TNF signaling pathways in HBV-ACLF. Antibody crosslinking of BTLA activates the PI3K-Akt pathway to inhibit CD4+ T cell activation, proliferation, and cytokine production while promoting apoptosis. BTLA knockdown promotes CD4+ T cell activation and proliferation. BTLA-/- ACLF mice show increased cytokine secretion and reduced mortality.\",\n      \"method\": \"BTLA crosslinking antibody assay, PI3K-Akt pathway analysis, BTLA knockdown (siRNA/shRNA), BTLA-/- mouse ACLF model, cytokine measurement\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse model, antibody crosslinking with defined signaling pathway, knockdown rescue, single lab\",\n      \"pmids\": [\"38418488\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Human BTLA is constitutively expressed on most CD4+ and CD8+ T cells and its expression progressively decreases upon T cell activation. Cross-linking BTLA with an agonistic monoclonal antibody inhibits T cell proliferation and production of IFN-γ and IL-10 in response to anti-CD3 stimulation, during both primary and secondary T cell responses.\",\n      \"method\": \"Anti-BTLA monoclonal antibody crosslinking, T cell proliferation assay, cytokine ELISA, flow cytometry\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — agonistic antibody crosslinking with functional readouts, replicated across multiple T cell response contexts\",\n      \"pmids\": [\"16643847\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"BTLA is an Ig superfamily co-inhibitory receptor that upon tyrosine phosphorylation recruits SHP-1 (predominantly) and SHP-2 via its ITIMs to suppress TCR and CD28 signaling; it also recruits Grb-2 and PI3K-p85 via a third cytoplasmic tyrosine motif to mediate a costimulatory/survival signal through Akt/PKB. Its sole ligand is HVEM (TNFRSF14), which it engages in a 1:1 complex at HVEM's CRD1 (structurally defined at 2.8 Å); BTLA and HVEM co-expressed on the same cell form an inhibitory cis-complex that blocks trans HVEM activation by other ligands (LIGHT, CD160) while preserving BTLA's inhibitory signaling. When presented in trans by dendritic cells, BTLA acts as an activating ligand for HVEM on T cells to promote CD8+ memory formation and Foxp3+ Treg induction via CD5 upregulation. BTLA signals through SHP-1 to reduce preformed CD40L mobilization at the immunological synapse and dampen T cell help to germinal center B cells; SHP-1/2-independent inhibitory mechanisms also exist. Defective BTLA function in SLE T cells results from impaired recruitment to the immunological synapse due to altered lipid metabolism, which can be pharmacologically corrected.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"BTLA is an immunoglobulin-superfamily co-inhibitory receptor that restrains adaptive and innate immune activation by dampening antigen-receptor signaling in T and B cells [#0, #24]. Following crosslinking with antigen receptors, BTLA becomes tyrosine-phosphorylated on its two ITIMs and recruits the phosphatases SHP-1 and SHP-2, attenuating IL-2 production and limiting T cell proliferation [#0]; quantitative interactomics in primary T cells establishes that BTLA preferentially recruits SHP-1, distinguishing its signalosome from the SHP-2-biased PD-1, while a phosphatase-independent inhibitory mechanism also operates [#4, #5]. A third cytoplasmic tyrosine motif recruits Grb-2 and, indirectly, the PI3K p85 subunit, mediating a costimulatory/pro-survival arm that drives Akt signaling, IL-2 secretion and TIL persistence [#2, #13, #14]. BTLA engages a single ligand, HVEM (TNFRSF14), forming a 1:1 complex at HVEM's N-terminal CRD1 through a binding surface shared with herpesvirus glycoprotein D and distinct from the LIGHT-binding surface [#1, #19, #20]. When co-expressed with HVEM on the same cell, BTLA forms an inhibitory cis-heterodimer that blocks HVEM oligomerization and trans engagement by LIGHT or CD160 while retaining its own inhibitory signaling, holding T cells in a naive state [#3, #18]. Presented in trans, BTLA also acts as an activating ligand for HVEM on T cells, delivering pro-survival signals that promote CD8+ effector/memory formation and extrathymic Foxp3+ Treg induction via CD5 upregulation [#8, #11, #12]. Physiologically, the BTLA-HVEM axis is an inhibitory checkpoint for dendritic-cell homeostasis, intestinal and hepatic inflammation, germinal-center T cell help, and γδ T cell expansion [#6, #7, #9, #10], and BTLA-mediated SHP-1/SHP-2 recruitment upon trans engagement with HVEM on regulatory T cells suppresses CAR T cells in tumors [#15].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established BTLA as a bona fide inhibitory receptor by linking its ITIMs to phosphatase recruitment and a defined proliferative phenotype, answering whether BTLA actively transduces a suppressive signal.\",\n      \"evidence\": \"Co-IP of SHP-1/SHP-2, phosphorylation assays, and BTLA-deficient T cell phenotyping\",\n      \"pmids\": [\"12796776\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve relative contribution of SHP-1 vs SHP-2\", \"Did not identify the ligand or costimulatory motif\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined the structural basis of BTLA-HVEM recognition, answering how an Ig-fold receptor engages a TNFR-family ligand and showing the binding surface overlaps with viral gD.\",\n      \"evidence\": \"X-ray crystallography at 2.8 Å with light scattering and alanine-scanning mutagenesis\",\n      \"pmids\": [\"16169851\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address cis vs trans geometry on cells\", \"Did not compare to CD160 or LIGHT binding sites\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identified a costimulatory arm of BTLA by mapping a third tyrosine motif recruiting Grb-2 and PI3K p85, revealing BTLA is not purely inhibitory.\",\n      \"evidence\": \"Synthetic phosphopeptide pulldown with mass spectrometry and direct binding confirmation\",\n      \"pmids\": [\"16725108\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, in vitro phosphopeptide system\", \"Functional consequence of Grb-2/PI3K recruitment not tested here\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Placed the BTLA-HVEM axis as an inhibitory checkpoint controlling dendritic-cell homeostasis and intestinal inflammation, extending its role beyond T cell-intrinsic signaling.\",\n      \"evidence\": \"Competitive bone marrow chimeras and adoptive T cell transfer colitis models with HVEM/BTLA KO mice\",\n      \"pmids\": [\"18097025\", \"18519647\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular source of HVEM and directionality of signaling not fully resolved\", \"Molecular mechanism downstream not defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined the cis-heterodimer mechanism, answering how BTLA-HVEM co-expression maintains naive T cells by competitively blocking trans HVEM activation.\",\n      \"evidence\": \"Reciprocal Co-IP, NF-κB reporter assays, genetic and pharmacologic disruption on human and mouse T cells\",\n      \"pmids\": [\"19915044\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of the cis-complex on the cell surface not quantified\", \"Did not resolve whether inhibitory signaling persists in cis\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrated BTLA functions bidirectionally as both a receptor and an HVEM ligand, with the ligand role delivering pro-survival signals independent of BTLA's own cytoplasmic signaling.\",\n      \"evidence\": \"Agonistic anti-BTLA antibody, signaling-domain deletion mutant, and GVHD mouse model; SPR/competition mapping of CD160 vs BTLA on HVEM\",\n      \"pmids\": [\"21220749\", \"21959263\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological settings favoring ligand vs receptor function not delineated\", \"Threshold for trans vs cis engagement unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Expanded BTLA's regulatory reach to γδ T cells and identified ROR\\u03b3t-mediated transcriptional control, and showed DC-expressed BTLA acts as a trans-activating ligand promoting CD8 memory.\",\n      \"evidence\": \"BTLA KO mice, ROR\\u03b3t AF-2 domain mutagenesis, IL-7 assays, and mixed adoptive transfer with vaccinia infection\",\n      \"pmids\": [\"24315996\", \"24205056\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Memory-promoting trans-ligand mechanism is inferred indirectly\", \"Coupling of transcriptional regulation to surface function incompletely defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Resolved that BTLA delivers dual outputs in CD8+ TILs—inhibiting division/cytokines while activating Akt-driven survival—through engagement by HVEM.\",\n      \"evidence\": \"HVEM ligand stimulation, Akt phosphorylation and apoptosis assays, in vivo TIL persistence tracking\",\n      \"pmids\": [\"26405566\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Did not map which cytoplasmic motif drives the Akt survival arm in this context\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected the BTLA-HVEM axis to peripheral tolerance by showing DC-expressed BTLA induces Foxp3+ Tregs via an HVEM\\u2192CD5\\u2192Foxp3 pathway in T cells.\",\n      \"evidence\": \"BTLA and HVEM KO mice, DC subset sorting, Treg induction and CD5/Foxp3 reporter assays\",\n      \"pmids\": [\"27793593\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biochemical link between HVEM engagement and CD5 upregulation not defined\", \"Relative contribution to peripheral tolerance in vivo not quantified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Functionally validated the Grb-2 motif as a costimulatory determinant in CD8+ T cells, tying the 2006 biochemistry to IL-2 output, Src activation, and TIL fitness.\",\n      \"evidence\": \"BTLA signaling-domain mutants, RPPA signaling analysis, and TCR-transgenic vaccination plus PDX models\",\n      \"pmids\": [\"28754817\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Balance between Grb-2 costimulation and ITIM inhibition context-dependence unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed that BTLA dysfunction in lupus arises from failed recruitment to the immunological synapse rather than loss of expression, identifying lipid metabolism as a correctable upstream defect.\",\n      \"evidence\": \"Synapse imaging, BTLA localization assays, and lipid-metabolism rescue in SLE patient primary CD4+ T cells\",\n      \"pmids\": [\"29997289\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Molecular link between lipid trafficking and BTLA synapse targeting not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Quantified the BTLA signalosome relative to PD-1, establishing SHP-1 dominance for BTLA versus SHP-2 dominance for PD-1 in primary effector T cells.\",\n      \"evidence\": \"SILAC quantitative interactomics at the T cell–APC interface in primary cells\",\n      \"pmids\": [\"31189114\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not test whether SHP-1 bias is required for differential potency in vivo\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined a tissue-level inhibitory mechanism whereby BTLA-SHP-1 signaling limits CD40L mobilization at the synapse to restrain germinal-center T cell help.\",\n      \"evidence\": \"T cell conditional BTLA KO, B cell HVEM KO, synapse imaging, SHP-1 assays and a lymphoma model\",\n      \"pmids\": [\"31204070\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism coupling SHP-1 to CD40L vesicle mobilization not biochemically resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated that BTLA retains potent inhibitory function in SHP1/SHP2 double-deficient T cells, establishing a phosphatase-independent suppressive mechanism.\",\n      \"evidence\": \"Reconstitution and SHP1/SHP2 double-knockout primary T cell signaling assays with proliferation/cytokine readouts\",\n      \"pmids\": [\"32437509\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the phosphatase-independent effector not determined\", \"Why inhibition is more transient without SHP1/2 unexplained\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Structurally and genetically separated HVEM's TNF-ligand and Ig-ligand engagement surfaces, linking BTLA/CD160 to control of liver inflammation versus LIGHT-driven bacterial clearance.\",\n      \"evidence\": \"Ternary HVEM-LIGHT-CD160 crystal structure and HVEM knockin mutant mice in infection and inflammation models\",\n      \"pmids\": [\"34709351\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not isolate BTLA-specific from CD160-specific contributions in vivo\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Clarified that within the cis-complex BTLA inhibition is dominant and preserved, while only LIGHT or CD160 (not BTLA) drive constitutive HVEM costimulation.\",\n      \"evidence\": \"T cell reporter systems with HVEM/ligand co-expression and primary human T cell stimulation assays\",\n      \"pmids\": [\"36081508\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Quantitative surface stoichiometry of cis-complex not measured\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Translated BTLA inhibition to engineered immunity, showing trans HVEM on Tregs recruits SHP-1/SHP-2 to BTLA on CAR T cells, and that BTLA knockout improves anti-tumor control.\",\n      \"evidence\": \"BTLA knockout CAR T cells, co-culture with HVEM+ Tregs, SHP recruitment assays, and in vivo lymphoma/solid tumor models\",\n      \"pmids\": [\"38831106\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address the phosphatase-independent inhibitory arm in CAR T cells\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular identity of BTLA's phosphatase-independent inhibitory effector and the rules governing the switch between its inhibitory receptor, costimulatory Grb-2/PI3K, and HVEM-ligand functions in vivo remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No effector identified for SHP-independent inhibition\", \"No unified model predicting cis-inhibition vs trans-ligand vs costimulatory outputs\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 24]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 4, 5]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [8, 11, 12]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 4, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 3, 24]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 6, 7, 11]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 3, 14]}\n    ],\n    \"complexes\": [\n      \"BTLA-HVEM cis-heterodimer\",\n      \"BTLA-SHP-1/SHP-2 signalosome\"\n    ],\n    \"partners\": [\n      \"HVEM\",\n      \"SHP-1\",\n      \"SHP-2\",\n      \"GRB2\",\n      \"PIK3R1\",\n      \"CD160\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}