Affinage

BTLA

B- and T-lymphocyte attenuator · UniProt Q7Z6A9

Length
289 aa
Mass
32.8 kDa
Annotated
2026-06-09
100 papers in source corpus 25 papers cited in narrative 25 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2003 High

    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

    PMID:12796776

    Open questions at the time
    • Did not resolve relative contribution of SHP-1 vs SHP-2
    • Did not identify the ligand or costimulatory motif
  2. 2005 High

    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

    PMID:16169851

    Open questions at the time
    • Did not address cis vs trans geometry on cells
    • Did not compare to CD160 or LIGHT binding sites
  3. 2006 Medium

    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

    PMID:16725108

    Open questions at the time
    • Single lab, in vitro phosphopeptide system
    • Functional consequence of Grb-2/PI3K recruitment not tested here
  4. 2008 High

    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

    PMID:18097025 PMID:18519647

    Open questions at the time
    • Cellular source of HVEM and directionality of signaling not fully resolved
    • Molecular mechanism downstream not defined
  5. 2009 High

    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

    PMID:19915044

    Open questions at the time
    • Stoichiometry of the cis-complex on the cell surface not quantified
    • Did not resolve whether inhibitory signaling persists in cis
  6. 2011 High

    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

    PMID:21220749 PMID:21959263

    Open questions at the time
    • Physiological settings favoring ligand vs receptor function not delineated
    • Threshold for trans vs cis engagement unclear
  7. 2013 Medium

    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

    PMID:24205056 PMID:24315996

    Open questions at the time
    • Memory-promoting trans-ligand mechanism is inferred indirectly
    • Coupling of transcriptional regulation to surface function incompletely defined
  8. 2015 Medium

    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

    PMID:26405566

    Open questions at the time
    • Single lab
    • Did not map which cytoplasmic motif drives the Akt survival arm in this context
  9. 2016 High

    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

    PMID:27793593

    Open questions at the time
    • Biochemical link between HVEM engagement and CD5 upregulation not defined
    • Relative contribution to peripheral tolerance in vivo not quantified
  10. 2017 Medium

    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

    PMID:28754817

    Open questions at the time
    • Single lab
    • Balance between Grb-2 costimulation and ITIM inhibition context-dependence unresolved
  11. 2018 Medium

    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

    PMID:29997289

    Open questions at the time
    • Single lab
    • Molecular link between lipid trafficking and BTLA synapse targeting not defined
  12. 2019 High

    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

    PMID:31189114

    Open questions at the time
    • Did not test whether SHP-1 bias is required for differential potency in vivo
  13. 2019 High

    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

    PMID:31204070

    Open questions at the time
    • Mechanism coupling SHP-1 to CD40L vesicle mobilization not biochemically resolved
  14. 2020 High

    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

    PMID:32437509

    Open questions at the time
    • Identity of the phosphatase-independent effector not determined
    • Why inhibition is more transient without SHP1/2 unexplained
  15. 2021 High

    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

    PMID:34709351

    Open questions at the time
    • Did not isolate BTLA-specific from CD160-specific contributions in vivo
  16. 2022 Medium

    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

    PMID:36081508

    Open questions at the time
    • Single lab
    • Quantitative surface stoichiometry of cis-complex not measured
  17. 2024 High

    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

    PMID:38831106

    Open questions at the time
    • Did not address the phosphatase-independent inhibitory arm in CAR T cells

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • No effector identified for SHP-independent inhibition
  • No unified model predicting cis-inhibition vs trans-ligand vs costimulatory outputs

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 3 GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3 GO:0060089 molecular transducer activity 2
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-168256 Immune System 4 R-HSA-162582 Signal Transduction 3
Partners
CD160GRB2HVEMPIK3R1SHP-1SHP-2
Complex memberships
BTLA-HVEM cis-heterodimerBTLA-SHP-1/SHP-2 signalosome

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 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. Co-immunoprecipitation, phosphorylation assay, BTLA-deficient mouse phenotyping, cytokine production assay Nature immunology High 12796776
2005 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. X-ray crystallography (2.8 Å), light scattering, alanine-scanning mutagenesis The Journal of biological chemistry High 16169851
2006 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. Synthetic phosphopeptide pulldown, mass spectrometry, direct binding confirmation Biochemical and biophysical research communications Medium 16725108
2009 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. Co-immunoprecipitation, NF-κB reporter assay, genetic deletion of BTLA, pharmacologic disruption, surface expression analysis on human and mouse T cells Journal of immunology High 19915044
2019 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. Quantitative mass spectrometry-based interactomics (SILAC), primary T cell biochemistry at the T cell–APC interface Cell reports High 31189114
2020 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. Reconstitution assays, primary T cell signaling assays, SHP1/SHP2 double-knockout T cells, proliferation and cytokine production readouts The Journal of cell biology High 32437509
2008 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. Competitive bone marrow chimeric mice, genetic deletion (HVEM-/-, BTLA-/- mice), spleen DC subset quantification Journal of immunology High 18097025
2008 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. Adoptive T cell transfer colitis model, HVEM-/- recipient vs donor analysis, Rag-/- bone marrow chimeras The Journal of experimental medicine High 18519647
2011 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. Agonistic anti-BTLA monoclonal antibody, BTLA signaling-domain deletion mutant, GVHD mouse model, survival and engraftment assays Blood High 21220749
2013 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. BTLA-deficient mice, RORγt AF-2 domain mutagenesis, IL-7 signaling assays, γδ T cell subset quantification, dermatitis disease model, cytokine production assays Immunity High 24315996
2013 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. BTLA conditional KO in T cells, HVEM KO in B cells, immunological synapse imaging, SHP-1 signaling assay, GC B cell quantification, lymphoma model Immunity High 31204070
2016 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. BTLA-deficient and HVEM-deficient mice, DC subset sorting, Treg induction assays, CD5 upregulation measurement, Foxp3 reporter Immunity High 27793593
2013 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. Mixed adoptive transfer of HVEM-/- and BTLA-/- T cells, vaccinia virus infection model, effector survival and memory quantification PloS one Medium 24205056
2017 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. BTLA signaling domain mutants, reverse-phase protein array (RPPA), antigen-specific vaccination models with TCR-transgenic T cells, patient-derived xenograft model Clinical cancer research Medium 28754817
2015 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. HVEM ligand stimulation assays, Akt/PKB phosphorylation assays, apoptosis assays, in vivo persistence tracking of TILs Oncoimmunology Medium 26405566
2024 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. 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 Nature immunology High 38831106
2012 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. BTLA-/- mice, MHV-3 infection model, adoptive macrophage transfer, TRAIL blocking, BTLA antibody treatment, cytokine and liver enzyme measurement Gut Medium 22637698
2012 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. BTLA/HVEM blocking antibodies, CpG-stimulated B cell functional assays, cytokine and chemokine measurement, B cell proliferation assay Journal of molecular medicine Medium 22903545
2022 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. T cell reporter systems, HVEM co-expression with various ligands, primary human T cell stimulation assays, HVEM antibody blocking Frontiers in immunology Medium 36081508
2021 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. X-ray crystallography (ternary complex), HVEM knockin mutant mice, bacterial infection models, liver inflammation models The Journal of experimental medicine High 34709351
2011 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. Surface plasmon resonance, N-terminal sequencing, mass spectrometry, HVEM mutagenesis, competitive binding assays Journal of molecular biology High 21959263
2018 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. Immunological synapse imaging, BTLA localization assay, lipid metabolism rescue experiments, T cell activation inhibition assay, SLE patient primary cells JCI insight Medium 29997289
2009 In vivo administration of anti-BTLA monoclonal antibody induces profound and lasting downmodulation of BTLA expression on lymphoid and myeloid cells through receptor internalization. In vivo mAb administration, flow cytometry, receptor internalization assay Immunobiology Low 19837478
2024 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. BTLA crosslinking antibody assay, PI3K-Akt pathway analysis, BTLA knockdown (siRNA/shRNA), BTLA-/- mouse ACLF model, cytokine measurement Nature communications Medium 38418488
2006 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. Anti-BTLA monoclonal antibody crosslinking, T cell proliferation assay, cytokine ELISA, flow cytometry Biochemical and biophysical research communications Medium 16643847

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 BTLA is a lymphocyte inhibitory receptor with similarities to CTLA-4 and PD-1. Nature immunology 693 12796776
2011 CD8(+) T cells specific for tumor antigens can be rendered dysfunctional by the tumor microenvironment through upregulation of the inhibitory receptors BTLA and PD-1. Cancer research 303 22205715
2006 Balancing co-stimulation and inhibition with BTLA and HVEM. Nature reviews. Immunology 258 16932752
2009 The CD160, BTLA, LIGHT/HVEM pathway: a bidirectional switch regulating T-cell activation. Immunological reviews 247 19426226
2009 BTLA mediates inhibition of human tumor-specific CD8+ T cells that can be partially reversed by vaccination. The Journal of clinical investigation 233 20038811
2010 Slow down and survive: Enigmatic immunoregulation by BTLA and HVEM. Annual review of immunology 188 20307212
2005 Attenuating lymphocyte activity: the crystal structure of the BTLA-HVEM complex. The Journal of biological chemistry 140 16169851
2009 HVEM/LIGHT/BTLA/CD160 cosignaling pathways as targets for immune regulation. Journal of leukocyte biology 133 20007250
2009 T cell intrinsic heterodimeric complexes between HVEM and BTLA determine receptivity to the surrounding microenvironment. Journal of immunology (Baltimore, Md. : 1950) 132 19915044
2019 Quantitative Interactomics in Primary T Cells Provides a Rationale for Concomitant PD-1 and BTLA Coinhibitor Blockade in Cancer Immunotherapy. Cell reports 129 31189114
2021 Roles of BTLA in Immunity and Immune Disorders. Frontiers in immunology 126 33859648
2016 Immunomodulatory Functions of BTLA and HVEM Govern Induction of Extrathymic Regulatory T Cells and Tolerance by Dendritic Cells. Immunity 122 27793593
2008 A crucial role for HVEM and BTLA in preventing intestinal inflammation. The Journal of experimental medicine 116 18519647
2020 PD-1 and BTLA regulate T cell signaling differentially and only partially through SHP1 and SHP2. The Journal of cell biology 101 32437509
2010 Regulation of inflammation, autoimmunity, and infection immunity by HVEM-BTLA signaling. Journal of leukocyte biology 93 21106644
2019 The HVEM-BTLA Axis Restrains T Cell Help to Germinal Center B Cells and Functions as a Cell-Extrinsic Suppressor in Lymphomagenesis. Immunity 90 31204070
2012 BTLA expression contributes to septic morbidity and mortality by inducing innate inflammatory cell dysfunction. Journal of leukocyte biology 87 22459947
2013 The co-receptor BTLA negatively regulates human Vγ9Vδ2 T-cell proliferation: a potential way of immune escape for lymphoma cells. Blood 82 23692853
2019 BTLA blockade enhances Cancer therapy by inhibiting IL-6/IL-10-induced CD19high B lymphocytes. Journal for immunotherapy of cancer 81 31753019
2006 Expression and function of the B and T lymphocyte attenuator (BTLA/CD272) on human T cells. Biochemical and biophysical research communications 79 16643847
2003 BTLA: a new inhibitory receptor with a B7-like ligand. Trends in immunology 78 14552835
2009 High expression of the inhibitory receptor BTLA in T-follicular helper cells and in B-cell small lymphocytic lymphoma/chronic lymphocytic leukemia. American journal of clinical pathology 77 19762537
2008 The inhibitory HVEM-BTLA pathway counter regulates lymphotoxin receptor signaling to achieve homeostasis of dendritic cells. Journal of immunology (Baltimore, Md. : 1950) 77 18097025
2013 The inhibitory receptor BTLA controls γδ T cell homeostasis and inflammatory responses. Immunity 74 24315996
2023 Beyond the anti-PD-1/PD-L1 era: promising role of the BTLA/HVEM axis as a future target for cancer immunotherapy. Molecular cancer 71 37649037
2012 PD-1 and BTLA and CD8(+) T-cell "exhaustion" in cancer: "Exercising" an alternative viewpoint. Oncoimmunology 71 22934265
2019 BTLA/HVEM Signaling: Milestones in Research and Role in Chronic Hepatitis B Virus Infection. Frontiers in immunology 70 30984188
2006 Association of Grb-2 and PI3K p85 with phosphotyrosile peptides derived from BTLA. Biochemical and biophysical research communications 69 16725108
2017 Multifaceted Role of BTLA in the Control of CD8+ T-cell Fate after Antigen Encounter. Clinical cancer research : an official journal of the American Association for Cancer Research 60 28754817
2013 Interfering with coinhibitory molecules: BTLA/HVEM as new targets to enhance anti-tumor immunity. Immunology letters 60 23439006
2010 Targeting of B and T lymphocyte associated (BTLA) prevents graft-versus-host disease without global immunosuppression. The Journal of experimental medicine 58 21078889
2009 Putting the brakes on BTLA in T cell-mediated cancer immunotherapy. The Journal of clinical investigation 57 20038807
2005 The evolving crosstalk between co-stimulatory and co-inhibitory receptors: HVEM-BTLA. Trends in immunology 56 15922943
2021 BTLA-HVEM Couple in Health and Diseases: Insights for Immunotherapy in Lung Cancer. Frontiers in oncology 55 34532285
2015 BTLA marks a less-differentiated tumor-infiltrating lymphocyte subset in melanoma with enhanced survival properties. Oncoimmunology 54 26405566
2017 Antibodies targeting BTLA or TIM-3 enhance HIV-1 specific T cell responses in combination with PD-1 blockade. Clinical immunology (Orlando, Fla.) 53 28882621
2015 Clinical significance of tumor-infiltrating immune cells focusing on BTLA and Cbl-b in patients with gallbladder cancer. Cancer science 53 26395180
2020 BTLA Expression in Stage I-III Non-Small-Cell Lung Cancer and Its Correlation with PD-1/PD-L1 and Clinical Outcomes. OncoTargets and therapy 52 32021268
2013 CD8 T cell memory to a viral pathogen requires trans cosignaling between HVEM and BTLA. PloS one 50 24205056
2007 Combined coinhibitory and costimulatory modulation with anti-BTLA and CTLA4Ig facilitates tolerance in murine islet allografts. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 48 17983390
2011 Dichotomous regulation of GVHD through bidirectional functions of the BTLA-HVEM pathway. Blood 44 21220749
2021 Combination checkpoint therapy with anti-PD-1 and anti-BTLA results in a synergistic therapeutic effect against murine glioblastoma. Oncoimmunology 43 34484870
2016 BTLA identifies dysfunctional PD-1-expressing CD4+ T cells in human hepatocellular carcinoma. Oncoimmunology 42 28123898
2006 BTLA and HVEM cross talk regulates inhibition and costimulation. Advances in immunology 40 17145304
2021 BTLA/HVEM Axis Induces NK Cell Immunosuppression and Poor Outcome in Chronic Lymphocytic Leukemia. Cancers 39 33917094
2009 Association of BTLA gene polymorphisms with the risk of malignant breast cancer in Chinese women of Heilongjiang Province. Breast cancer research and treatment 39 19585237
2024 The BTLA-HVEM axis restricts CAR T cell efficacy in cancer. Nature immunology 38 38831106
2018 Distinct Changes of BTLA and HVEM Expressions in Circulating CD4+ and CD8+ T Cells in Hepatocellular Carcinoma Patients. Journal of immunology research 38 30116751
2016 B Lymphocytes in Multiple Sclerosis: Bregs and BTLA/CD272 Expressing-CD19+ Lymphocytes Modulate Disease Severity. Scientific reports 37 27412504
2006 Association of a BTLA gene polymorphism with the risk of rheumatoid arthritis. Journal of biomedical science 37 17024343
2024 BTLA biology in cancer: from bench discoveries to clinical potentials. Biomarker research 36 38233898
2022 BTLA inhibition has a dominant role in the cis-complex of BTLA and HVEM. Frontiers in immunology 36 36081508
2018 BTLA marks a less cytotoxic T-cell subset in diffuse large B-cell lymphoma with high expression of checkpoints. Experimental hematology 36 29353075
2018 Defective BTLA functionality is rescued by restoring lipid metabolism in lupus CD4+ T cells. JCI insight 36 29997289
2011 Molecular basis for herpesvirus entry mediator recognition by the human immune inhibitory receptor CD160 and its relationship to the cosignaling molecules BTLA and LIGHT. Journal of molecular biology 36 21959263
2010 Circulating CD4+CD25high regulatory T cells and expression of PD-1 and BTLA on CD4+ T cells in patients with chronic hepatitis B virus infection. Viral immunology 36 20121403
2013 A novel nanoparticle containing MOG peptide with BTLA induces T cell tolerance and prevents multiple sclerosis. Molecular immunology 35 24084097
2024 BTLA contributes to acute-on-chronic liver failure infection and mortality through CD4+ T-cell exhaustion. Nature communications 33 38418488
2021 Genetic signature of CTLA-4, BTLA, TIM-3 and LAG-3 molecular expression in colorectal cancer patients: Implications in diagnosis and survival outcomes. Clinical biochemistry 33 34217699
2019 BTLA Expression on Th1, Th2 and Th17 Effector T-Cells of Patients with Systemic Lupus Erythematosus Is Associated with Active Disease. International journal of molecular sciences 33 31514450
2015 Cutting Edge: the BTLA-HVEM regulatory pathway interferes with protective immunity to intestinal Helminth infection. Journal of immunology (Baltimore, Md. : 1950) 33 25595777
2009 Detection of protein on BTLAlow cells and in vivo antibody-mediated down-modulation of BTLA on lymphoid and myeloid cells of C57BL/6 and BALB/c BTLA allelic variants. Immunobiology 33 19837478
2018 Downregulation of BTLA on NKT Cells Promotes Tumor Immune Control in a Mouse Model of Mammary Carcinoma. International journal of molecular sciences 32 29518903
2016 Enhanced Innate Inflammation Induced by Anti-BTLA Antibody in Dual Insult Model of Hemorrhagic Shock/Sepsis. Shock (Augusta, Ga.) 32 26674453
2012 Expression of B and T lymphocyte attenuator (BTLA) in macrophages contributes to the fulminant hepatitis caused by murine hepatitis virus strain-3. Gut 32 22637698
2007 Negative and positive co-signaling with anti-BTLA (PJ196) and CTLA4Ig prolongs islet allograft survival. Transplantation 30 18049125
2020 Abnormal Expression of BTLA and CTLA-4 Immune Checkpoint Molecules in Chronic Lymphocytic Leukemia Patients. Journal of immunology research 29 32775467
2009 BTLA targeting modulates lymphocyte phenotype, function, and numbers and attenuates disease in nonobese diabetic mice. Journal of leukocyte biology 29 19383625
2017 Design of short peptides to block BTLA/HVEM interactions for promoting anticancer T-cell responses. PloS one 28 28594868
2020 A combination of the activation marker CD86 and the immune checkpoint marker B and T lymphocyte attenuator (BTLA) indicates a putative permissive activation state of B cell subtypes in healthy blood donors independent of age and sex. BMC immunology 27 32197584
2020 BTLA-Expressing Dendritic Cells in Patients With Tuberculosis Exhibit Reduced Production of IL-12/IFN-α and Increased Production of IL-4 and TGF-β, Favoring Th2 and Foxp3+ Treg Polarization. Frontiers in immunology 27 32296431
2019 Divergent LAG-3 versus BTLA, TIGIT, and FCRL3 expression in Sézary syndrome. Leukemia & lymphoma 27 30638415
2018 Herpes Simplex Virus 1 Latency and the Kinetics of Reactivation Are Regulated by a Complex Network of Interactions between the Herpesvirus Entry Mediator, Its Ligands (gD, BTLA, LIGHT, and CD160), and the Latency-Associated Transcript. Journal of virology 27 30282707
2019 BTLA suppress acute rejection via regulating TCR downstream signals and cytokines production in kidney transplantation and prolonged allografts survival. Scientific reports 26 31434927
2021 HVEM structures and mutants reveal distinct functions of binding to LIGHT and BTLA/CD160. The Journal of experimental medicine 25 34709351
2012 CpG-ODN-induced sustained expression of BTLA mediating selective inhibition of human B cells. Journal of molecular medicine (Berlin, Germany) 24 22903545
2024 The BTLA-HVEM complex - The future of cancer immunotherapy. European journal of medicinal chemistry 23 38387336
2020 Disulfide-Linked Peptides for Blocking BTLA/HVEM Binding. International journal of molecular sciences 23 31963646
2014 BTLA exhibits immune memory for αβ T cells in patients with active pulmonary tuberculosis. American journal of translational research 23 25360214
2003 Identification and disruption of btlA, a locus involved in bile tolerance and general stress resistance in Listeria monocytogenes. FEMS microbiology letters 23 12583894
2020 Correlations of the expression of γδ T cells and their co-stimulatory molecules TIGIT, PD-1, ICOS and BTLA with PR and PIBF in the peripheral blood and decidual tissues of women with unexplained recurrent spontaneous abortion. Clinical and experimental immunology 22 33017473
2007 IMGT Colliers de Perles and IgSF domain standardization for T cell costimulatory activatory (CD28, ICOS) and inhibitory (CTLA4, PDCD1 and BTLA) receptors. Developmental and comparative immunology 22 17391759
2016 Association of 3' nearby gene BTLA polymorphisms with the risk of renal cell carcinoma in the Polish population. Urologic oncology 21 27234378
2016 Hepatic expansion of virus-specific CD8+BTLA+ T cells with regulatory properties in chronic hepatitis B virus infection. Cellular immunology 21 27743606
2016 BTLA-expressing CD11c antigen presenting cells in patients with active tuberculosis exhibit low capacity to stimulate T cell proliferation. Cellular immunology 20 27717503
2016 Intragenic Variations in BTLA Gene Influence mRNA Expression of BTLA Gene in Chronic Lymphocytic Leukemia Patients and Confer Susceptibility to Chronic Lymphocytic Leukemia. Archivum immunologiae et therapiae experimentalis 20 27933341
2012 The intrahepatic expression and distribution of BTLA and its ligand HVEM in patients with HBV-related acute-on-chronic liver failure. Diagnostic pathology 20 23067542
2020 Fragments of gD Protein as Inhibitors of BTLA/HVEM Complex Formation-Design, Synthesis, and Cellular Studies. International journal of molecular sciences 19 33238640
2020 The BTLA and PD-1 signaling pathways independently regulate the proliferation and cytotoxicity of human peripheral blood γδ T cells. Immunity, inflammation and disease 19 33332777
2012 The expression and anatomical distribution of BTLA and its ligand HVEM in rheumatoid synovium. Inflammation 19 22179929
2005 BTLA, a new inhibitory B7 family receptor with a TNFR family ligand. Cellular & molecular immunology 19 16426492
2021 Combined Immunotherapy With Belatacept and BTLA Overexpression Attenuates Acute Rejection Following Kidney Transplantation. Frontiers in immunology 18 33732243
2021 BTLA Expression and Function Are Impaired on SLE B Cells. Frontiers in immunology 18 33968071
2020 Association between BTLA polymorphisms and susceptibility to esophageal squamous cell carcinoma in the Chinese population. Journal of clinical laboratory analysis 18 32060969
2017 Adenovirus-Mediated CCR7 and BTLA Overexpression Enhances Immune Tolerance and Migration in Immature Dendritic Cells. BioMed research international 18 28393074
2016 BTLA+ Dendritic Cells: The Regulatory T Cell Force Awakens. Immunity 18 27851922
2013 BTLA as a biomarker and mediator of sepsis-induced immunosuppression. Critical care (London, England) 18 24321139
2016 Regulatory T Cell Dysfunction Acquiesces to BTLA+ Regulatory B Cells Subsequent to Oral Intervention in Experimental Autoimmune Encephalomyelitis. Journal of immunology (Baltimore, Md. : 1950) 17 27194787
2015 BTLA expression declines on B cells of the aged and is associated with low responsiveness to the trivalent influenza vaccine. Oncotarget 17 26277622
2009 Modulation of T cell proliferation through the LIGHT-HVEM-BTLA cosignaling pathway. Recent patents on DNA & gene sequences 16 19702559

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