Affinage

BTLA

B- and T-lymphocyte attenuator · UniProt Q7Z6A9

Length
289 aa
Mass
32.8 kDa
Annotated
2026-04-28
100 papers in source corpus 23 papers cited in narrative 22 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

BTLA is an immunoglobulin superfamily coinhibitory receptor that functions as a central regulator of adaptive and innate immune cell activation, restraining T cell, B cell, dendritic cell, and macrophage responses through both receptor-intrinsic inhibitory signaling and bidirectional communication with its ligand HVEM. Upon engagement by HVEM in trans or crosslinking with the antigen receptor, BTLA undergoes tyrosine phosphorylation at its ITIM/ITSM motifs and preferentially recruits the phosphatase SHP-1 (and to a lesser extent SHP-2) to suppress TCR, CD28, and BCR signaling, thereby inhibiting proliferation, cytokine production, and CD40L mobilization to the immunological synapse (PMID:12796776, PMID:31189114, PMID:31204070); an additional SHP-1/SHP-2-independent inhibitory mechanism also operates (PMID:32437509). BTLA simultaneously acts as a ligand for HVEM: on naive T cells it forms a cis-heterodimeric complex with HVEM that blocks HVEM costimulation and maintains quiescence (PMID:19915044, PMID:36081508), while in trans BTLA on dendritic cells delivers NF-κB-dependent pro-survival signals through HVEM on T cells, promoting regulatory T cell differentiation, effector CD8+ T cell memory, and CD5-dependent Foxp3 induction (PMID:24205056, PMID:27793593, PMID:21220749). A third tyrosine motif in the BTLA cytoplasmic tail recruits Grb2 and mediates a costimulatory function in CD8+ T cells that enhances IL-2 production and Src activation (PMID:16725108, PMID:28754817).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2003 High

    Identification of BTLA as a novel ITIM-bearing inhibitory receptor resolved the question of whether additional immunoglobulin-family coinhibitory molecules beyond CTLA-4 and PD-1 existed, establishing that BTLA recruits SHP-1 and SHP-2 upon phosphorylation to attenuate T cell activation and antibody responses.

    Evidence BTLA-knockout mice, co-immunoprecipitation, IL-2 production assays, EAE susceptibility model

    PMID:12796776

    Open questions at the time
    • Ligand for BTLA unknown at this stage
    • Relative contribution of SHP-1 vs SHP-2 not resolved
    • Mechanism of action in B cells not directly tested
  2. 2005 High

    Structural determination of the BTLA–HVEM complex revealed that an Ig-superfamily receptor binds a TNF receptor superfamily member — an unprecedented cross-family interaction — establishing the molecular basis for BTLA engagement and showing BTLA binds CRD1 of HVEM as a 1:1 monomer.

    Evidence X-ray crystallography at 2.8 Å, light scattering, alanine-scanning mutagenesis of HVEM

    PMID:16169851

    Open questions at the time
    • Whether BTLA and LIGHT can simultaneously engage HVEM not resolved
    • In vivo significance of identified contact residues untested
  3. 2006 Medium

    Discovery of a Grb2-binding tyrosine motif in BTLA's cytoplasmic tail, beyond the canonical ITIMs, revealed an unexpected signaling complexity suggesting BTLA could transmit both inhibitory and costimulatory signals depending on context.

    Evidence Phosphopeptide pulldown with mass spectrometry, direct binding assays identifying Grb2 and indirect PI3K p85 recruitment

    PMID:16725108

    Open questions at the time
    • Functional consequence of Grb2 recruitment in T cells not yet demonstrated
    • Whether Grb2 motif operates independently of ITIMs unclear
  4. 2008 High

    In vivo studies using bone marrow chimeras and adoptive transfer colitis models established that the BTLA–HVEM axis operates bidirectionally in distinct immune compartments — restraining T cell-mediated intestinal inflammation and controlling dendritic cell homeostasis by counter-regulating LTβR signaling.

    Evidence Competitive bone marrow chimeras, HVEM/BTLA-knockout recipients, adoptive T cell transfer colitis model

    PMID:18097025 PMID:18519647

    Open questions at the time
    • Molecular mechanism linking BTLA to LTβR counter-regulation in DCs not defined
    • Whether BTLA acts as receptor or ligand on DCs in homeostasis unclear
  5. 2009 High

    Discovery of the BTLA–HVEM cis-complex on naive T cells revealed a cell-autonomous mechanism by which BTLA blocks HVEM costimulation and maintains T cell quiescence, answering how HVEM can be silenced despite constitutive expression on resting cells.

    Evidence Cell surface binding assays, NF-κB reporter systems, genetic deletion of BTLA, pharmacologic disruption

    PMID:19915044

    Open questions at the time
    • How the cis-complex is disrupted during activation not fully resolved
    • Whether cis-complex affects BTLA's own inhibitory signaling unknown
  6. 2011 High

    Using a BTLA cytoplasmic-truncation mutant in GVHD, BTLA was shown to function as a trans-activating ligand for HVEM independently of its own intracellular signaling, establishing a bidirectional signaling paradigm in which BTLA delivers pro-survival signals to adjacent HVEM-expressing T cells.

    Evidence BTLA intracellular domain-deletion mutant, agonistic anti-BTLA antibody, GVHD mouse model

    PMID:21220749

    Open questions at the time
    • Whether ligand function requires specific BTLA ectodomain residues not mapped
    • Downstream NF-κB-dependent targets in HVEM-expressing cells not defined
  7. 2012 High

    BTLA's functional scope was extended beyond lymphocytes: in macrophages BTLA promotes survival during viral hepatitis (its absence causes TRAIL-dependent apoptosis), and in B cells BTLA–HVEM interaction selectively inhibits TLR9-driven proliferation and cytokine production without affecting chemokine secretion.

    Evidence BTLA-KO mice with MHV-3 infection and macrophage adoptive transfer; CpG-stimulated human B cells with BTLA/HVEM blocking antibodies

    PMID:22637698 PMID:22903545

    Open questions at the time
    • How BTLA selectively inhibits certain TLR9-driven outputs but not others is unknown
    • Whether BTLA pro-survival signaling in macrophages is SHP-dependent or HVEM-dependent unclear
  8. 2013 High

    Mechanistic studies revealed that BTLA on CD8α+ DCs serves as a trans-ligand for HVEM on CD8+ T cells to promote effector survival and memory formation, and that RORγt transcriptionally represses Btla to license γδ T cell expansion and IL-17 production, establishing BTLA as a transcriptionally regulated checkpoint in innate-like lymphocytes.

    Evidence Mixed adoptive transfer with HVEM/BTLA-KO mice in vaccinia infection; RORγt AF-2 domain mutants, BTLA-deficient γδ T cell analysis in dermatitis model

    PMID:24205056 PMID:24205057 PMID:24315996

    Open questions at the time
    • Whether BTLA ligand function on DCs requires phosphorylation of BTLA not tested
    • How RORγt AF-2 domain mediates Btla repression at the chromatin level undefined
  9. 2016 High

    The trans-ligand function of BTLA on DCs was linked to extrathymic Treg differentiation: BTLA engagement of HVEM on T cells upregulates CD5, which protects Foxp3 induction from suppression by effector-differentiating cytokines, placing BTLA at the nexus of peripheral tolerance.

    Evidence DC subset purification and T cell co-culture, BTLA/HVEM-KO mice, Foxp3 and CD5 expression analysis, in vivo tolerance models

    PMID:27793593

    Open questions at the time
    • Signaling intermediates between HVEM engagement and CD5 upregulation not identified
    • Whether this mechanism operates in human Treg induction untested
  10. 2017 Medium

    The Grb2-binding motif of BTLA was functionally dissected in CD8+ T cells, revealing it delivers a costimulatory signal that enhances IL-2 secretion and Src activation, with BTLA+ TILs showing improved serial killing capacity — resolving how the same receptor can provide both inhibitory and costimulatory inputs.

    Evidence BTLA signaling motif mutants (ITIM/ITSM vs Grb2), RPPA signaling arrays, antigen-specific vaccination models, PDX tumor models

    PMID:28754817

    Open questions at the time
    • How Grb2-motif costimulation integrates with ITIM-mediated inhibition in the same cell is not quantitatively modeled
    • Whether the costimulatory function is relevant in CD4+ T cells or other lineages unknown
  11. 2019 High

    Quantitative interactomics in primary T cells definitively established SHP-1 as the dominant BTLA phosphatase partner (distinguishing it from PD-1's SHP-2 preference), and conditional BTLA deletion in T cells showed that BTLA suppresses CD40L delivery to the immunological synapse, restraining germinal center B cell expansion and lymphomagenesis.

    Evidence AP-MS interactomics in primary T cells; conditional KO mice with Bcl-2 transgenic cooperation, immunological synapse imaging

    PMID:31189114 PMID:31204070

    Open questions at the time
    • Whether SHP-1 and SHP-2 have non-redundant substrates downstream of BTLA not resolved
    • The SHP-independent inhibitory mechanism remains molecularly undefined
  12. 2020 High

    Generation of SHP-1/SHP-2 double-deficient T cells revealed that BTLA retains potent inhibitory function even without both phosphatases, proving the existence of a SHP-independent signaling arm whose molecular basis remains unknown.

    Evidence SHP1/SHP2 double-deficient primary T cells, reconstitution assays, proliferation and cytokine assays

    PMID:32437509

    Open questions at the time
    • Identity of the SHP-independent effector(s) is unknown
    • Whether this mechanism operates in non-T cells not addressed
  13. 2021 High

    Crystal structures of the ternary HVEM–LIGHT–CD160/BTLA complex showed that HVEM can simultaneously engage TNF-family and Ig-family ligands on distinct surfaces, and knockin mouse mutants selectively disrupting each interface demonstrated that Ig ligands (BTLA/CD160) specifically ameliorate liver inflammation while LIGHT controls bacterial clearance.

    Evidence X-ray crystallography of human ternary complex, site-directed mutagenesis, HVEM knockin mouse models, in vivo infection and inflammation

    PMID:34709351

    Open questions at the time
    • Whether BTLA and CD160 have non-redundant roles in the Ig-ligand arm not separated
    • Structural basis for how the cis-complex is regulated during T cell activation unclear
  14. 2022 Medium

    Reporter and primary T cell assays clarified that within the cis-complex, BTLA's inhibitory function remains fully active and dominant, while HVEM costimulatory signaling is specifically induced by CD160 or LIGHT but not BTLA in cis, resolving how cis and trans signaling modes are segregated.

    Evidence T cell reporter systems, primary human T cell stimulation, co-expression studies with HVEM ligands

    PMID:36081508

    Open questions at the time
    • How BTLA cis-inhibition is overridden during strong activation signals unknown
    • Translation to in vivo settings not yet demonstrated
  15. 2024 High

    Translational studies demonstrated that BTLA-mediated inhibition is a functional checkpoint in CAR T cell therapy (where HVEM on Tregs engages BTLA to suppress anti-tumor activity) and in hepatitis-associated acute-on-chronic liver failure (where IL-6/TNF upregulate BTLA on CD4+ T cells to activate PI3K-Akt-mediated suppression), establishing BTLA as a therapeutic target in both cancer and inflammatory liver disease.

    Evidence BTLA-KO CAR T cells in lymphoma/solid tumor models; BTLA crosslinking with PI3K-Akt pathway analysis, BTLA-KO ACLF mouse model

    PMID:38418488 PMID:38831106

    Open questions at the time
    • Whether BTLA deletion in CAR T cells affects long-term persistence and exhaustion not fully assessed
    • The PI3K-Akt pathway activation by BTLA crosslinking in hepatitis appears paradoxical relative to its inhibitory function and requires mechanistic clarification

Open questions

Synthesis pass · forward-looking unresolved questions
  • The molecular identity of the SHP-1/SHP-2-independent inhibitory effector downstream of BTLA remains unknown, and how the Grb2-mediated costimulatory and ITIM-mediated inhibitory signals are integrated within the same cell to determine net signaling outcome is unresolved.
  • SHP-independent effector unidentified
  • Quantitative model of costimulatory vs inhibitory signal integration lacking
  • Structural basis for cis-to-trans complex transition during T cell activation undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0060090 molecular adaptor activity 3
Localization
GO:0005886 plasma membrane 4
Pathway
R-HSA-168256 Immune System 6 R-HSA-162582 Signal Transduction 4
Partners
CD160GRB2PTPN11PTPN6TNFRSF14TNFSF14
Complex memberships
BTLA-HVEM cis-complexBTLA-SHP-1 signalosome

Evidence

Reading pass · 22 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 tyrosine phosphorylation and association with SHP-1 and SHP-2, attenuating IL-2 production. BTLA-deficient T cells show increased proliferation and BTLA-deficient mice have increased antibody responses and enhanced EAE susceptibility. Co-immunoprecipitation, phosphorylation assays, BTLA-knockout mouse phenotyping, cytokine production assays Nature immunology High 12796776
2005 Crystal structure of the BTLA-HVEM complex at 2.8 Å shows BTLA binds the N-terminal cysteine-rich domain 1 (CRD1) of HVEM, employing a unique binding surface compared with other CD28-like receptors; BTLA adopts an immunoglobulin I-set fold; light scattering demonstrates BTLA ectodomain is monomeric and forms a 1:1 complex with HVEM. Alanine-scanning mutagenesis of HVEM defined critical binding residues. BTLA recognizes the same HVEM surface as herpesvirus glycoprotein D (gD). X-ray crystallography (2.8 Å), light scattering analysis, alanine-scanning mutagenesis The Journal of biological chemistry High 16169851
2006 BTLA cytoplasmic domain contains a third conserved tyrosine motif resembling a Grb-2 recruitment site; phosphopeptide pulldown with mass spectrometry identified Grb-2 and the p85 subunit of PI3K as interacting proteins. Grb-2 binds directly to the phosphotyrosine-containing peptide, whereas p85 recruitment is indirect via its association with Grb-2. Phosphotyrosine peptide pulldown, mass spectrometry, direct binding assays Biochemical and biophysical research communications Medium 16725108
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 mAb inhibits T cell proliferation and cytokine (IFN-γ and IL-10) production in response to anti-CD3 stimulation, demonstrating a constitutive inhibitory function. Monoclonal antibody cross-linking, T cell proliferation assays, cytokine production assays, flow cytometry Biochemical and biophysical research communications Medium 16643847
2009 BTLA interacts with HVEM in cis on the surface of naive T cells, forming a heterodimeric complex that inhibits HVEM-dependent NF-κB activation. The BTLA ectodomain acts as a competitive inhibitor, blocking BTLA and CD160 from binding HVEM in trans and initiating NF-κB activation. LIGHT can bind within the cis-complex but NF-κB activation is attenuated, suggesting BTLA prevents HVEM oligomerization. Cell surface binding assays, NF-κB reporter assays, genetic deletion of BTLA, pharmacologic disruption of cis-complex, T cell reporter systems Journal of immunology High 19915044
2008 The HVEM-BTLA inhibitory pathway counter-regulates lymphotoxin receptor (LTβR) signaling to achieve dendritic cell homeostasis. HVEM- and BTLA-deficient mice show overpopulation of CD8α- DC subsets with a growth advantage in competitive bone marrow chimeras. DC expression of both HVEM and BTLA, as well as LTβR, is required for homeostasis. Competitive bone marrow chimeras, knockout mouse analysis, flow cytometry of DC subsets, agonist antibody treatment Journal of immunology High 18097025
2008 In a T cell transfer colitis model, HVEM on radioresistant (non-T) cells in recipient mice interacts with BTLA to prevent intestinal inflammation, demonstrating that HVEM expressed by innate immune cells exerts anti-inflammatory effects through BTLA-mediated coinhibitory signaling. Adoptive T cell transfer colitis model, bone marrow chimeras, HVEM/BTLA knockout recipients The Journal of experimental medicine High 18519647
2011 In GVHD, BTLA serves dual roles: (1) as a receptor that delivers inhibitory signals inhibiting donor anti-host T cell responses when stimulated by an agonistic anti-BTLA antibody, and (2) as a ligand that activates HVEM pro-survival signaling in donor T cells independently of its intracellular signaling domain, as shown by a BTLA cytoplasmic-truncation mutant restoring survival of BTLA-deficient T cells. Agonistic anti-BTLA antibody, BTLA intracellular domain-deletion mutant, GVHD mouse model, survival assays Blood High 21220749
2013 BTLA expression on CD8α+ dendritic cells functions as a trans-activating ligand delivering positive co-signals through HVEM expressed on CD8+ T cells, promoting effector CD8 T cell survival and memory formation in vaccinia virus infection. Mixed adoptive transfer experiments demonstrate the cell-type requirement. Mixed adoptive transfer, HVEM/BTLA knockout mouse models, viral infection model, memory T cell quantification PloS one High 24205056 24205057
2013 In γδ T cells, BTLA expression is regulated by the transcription factor RORγt (which represses Btla transcription via its AF-2 domain) and IL-7 (which increases BTLA surface levels). BTLA limits γδ T cell numbers by restricting IL-7-responsiveness and negatively regulates IL-17 and TNF production in CD27- γδ T cells. BTLA-deficient mice, RORγt AF-2 domain mutants, IL-7 stimulation assays, dermatitis mouse model, BTLA agonism Immunity High 24315996
2016 BTLA+DEC205+CD8+CD11c+ dendritic cells efficiently induce extrathymic regulatory T (Treg) cell differentiation. Engagement of HVEM on T cells by BTLA on DCs promotes Foxp3 expression via upregulation of CD5, which enables T cells to resist inhibition of Foxp3 by effector-differentiating cytokines. DC subset purification and T cell co-culture, BTLA/HVEM knockout mice, Foxp3 and CD5 expression analysis, in vivo tolerance models Immunity High 27793593
2018 BTLA function is impaired in lupus CD4+ T cells due to defective recruitment of BTLA to the immunological synapse following T cell stimulation; this defect can be corrected by restoring intracellular lipid metabolism and trafficking in SLE T cells. Immunological synapse imaging, BTLA localization assays, lipid metabolism rescue experiments, functional T cell assays JCI insight Medium 29997289
2019 Quantitative interactomics in primary T cells shows BTLA predominantly recruits SHP-1 (and to a lesser extent SHP-2) to form its coinhibitory signalosome, in contrast to PD-1 which predominantly recruits SHP-2. Both BTLA-SHP-1 and PD-1-SHP-2 complexes equally dampen TCR and CD28 signaling pathways. Quantitative mass spectrometry interactomics (AP-MS) in primary T cells, T cell-APC interface analysis Cell reports High 31189114
2019 BTLA signaling into T cells through SHP1 reduces TCR signaling and preformed CD40 ligand mobilization to the immunological synapse, 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, establishing BTLA as a cell-extrinsic suppressor of GC B cell lymphomagenesis. BTLA conditional knockout mice, immunological synapse imaging, TCR signaling assays, CD40L mobilization assays, GC response analysis, Bcl-2 transgenic cooperation Immunity High 31204070
2020 BTLA preferentially recruits SHP-1 over SHP-2 to suppress T cell signaling more efficiently than PD-1. In SHP1/SHP2 double-deficient primary T cells, both PD-1 and BTLA still potently inhibit proliferation and cytokine production, demonstrating that both receptors can also suppress T cell signaling through a mechanism independent of SHP1 and SHP2. SHP1/SHP2 double-deficient primary T cells, reconstitution assays, T cell proliferation and cytokine assays, phosphatase recruitment comparison The Journal of cell biology High 32437509
2021 Crystal structures reveal HVEM simultaneously interacts with LIGHT via one surface and with BTLA/CD160 via the distinct CRD1 surface, forming a ternary complex. Mouse HVEM knockin mutants selectively recognizing either TNF or Ig ligands demonstrate selective in vivo functions: LIGHT drives clearance of intestinal bacteria, while Ig ligands (BTLA/CD160) ameliorate liver inflammation. X-ray crystallography (human HVEM-LIGHT-CD160 ternary complex), site-directed mutagenesis, knockin mouse models, in vivo infection and inflammation models The Journal of experimental medicine High 34709351
2022 In the BTLA-HVEM cis-complex on T cells, BTLA-mediated inhibition is not impaired; co-expression with LIGHT or CD160 (but not BTLA) induces strong constitutive HVEM signaling. BTLA inhibition is dominant in the heterodimeric cis-complex, and HVEM antibodies can simultaneously act as checkpoint inhibitors and costimulation agonists. T cell reporter systems, primary human T cell stimulation assays, co-expression studies with HVEM ligands Frontiers in immunology Medium 36081508
2024 BTLA inhibits CAR T cells via recruitment of tyrosine phosphatases SHP-1 and SHP-2 upon trans engagement with HVEM on regulatory T cells in the tumor microenvironment. Deletion of BTLA in CAR T cells improves tumor control and persistence in lymphoma and solid tumor models. BTLA knockout CAR T cells, phosphatase recruitment assays, mouse lymphoma and solid tumor models, CAR T cell functional assays Nature immunology High 38831106
2024 BTLA levels are upregulated on CD4+ T cells from HBV-ACLF patients by IL-6 and TNF signaling pathways. Antibody crosslinking of BTLA activates the PI3K-Akt pathway to inhibit activation, proliferation, and cytokine production of CD4+ T cells while promoting apoptosis. BTLA knockdown promotes CD4+ T cell activation and proliferation. BTLA-/- ACLF mice show increased cytokine secretion and reduced mortality and bacterial burden. BTLA antibody crosslinking, PI3K-Akt pathway activation assays, BTLA knockdown, BTLA-knockout ACLF mouse model, anti-BTLA neutralizing antibody treatment Nature communications High 38418488
2017 The Grb2-binding motif of BTLA mediates a costimulatory function in CD8+ T cells by enhancing IL-2 secretion and Src activation after TCR stimulation. BTLA+ CD8+ TILs show improved survival following tumor target killing and enhanced serial killing capacity; BTLA- TILs have impaired recall responses to vaccination. BTLA signaling motif mutants (ITIM/ITSM vs Grb2 motif), RPPA signaling arrays, antigen-specific vaccination models, adoptive transfer with TCR-transgenic T cells, PDX tumor models Clinical cancer research Medium 28754817
2012 BTLA expression in macrophages promotes the pathogenesis of virus-induced fulminant hepatitis by enhancing macrophage viability. BTLA-/- mice show rapid TRAIL-dependent apoptosis of MHV-3-infected macrophages, resulting in reduced TNFα, FGL2, viral titers, and improved survival. Adoptive transfer of macrophages to BTLA-/- mice restores sensitivity. BTLA-knockout mouse model, MHV-3 infection, macrophage adoptive transfer, BTLA blockade, TRAIL-dependent apoptosis assays, cytokine measurements Gut High 22637698
2012 BTLA interaction with HVEM inhibits CpG (TLR9)-mediated B cell functions including proliferation, cytokine production, and upregulation of co-stimulatory molecules; this inhibition is reversed by blocking BTLA/HVEM interactions. Chemokine secretion (IL-8 and MIP1β) is not affected, showing BTLA-mediated inhibition is selective for certain B cell functions. CpG stimulation of human B cells, BTLA/HVEM blocking antibodies, functional assays for proliferation and cytokine production Journal of molecular medicine Medium 22903545

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 691 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 302 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
2010 Slow down and survive: Enigmatic immunoregulation by BTLA and HVEM. Annual review of immunology 187 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) 131 19915044
2019 Quantitative Interactomics in Primary T Cells Provides a Rationale for Concomitant PD-1 and BTLA Coinhibitor Blockade in Cancer Immunotherapy. Cell reports 128 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 121 27793593
2008 A crucial role for HVEM and BTLA in preventing intestinal inflammation. The Journal of experimental medicine 115 18519647
2020 PD-1 and BTLA regulate T cell signaling differentially and only partially through SHP1 and SHP2. The Journal of cell biology 96 32437509
2010 Regulation of inflammation, autoimmunity, and infection immunity by HVEM-BTLA signaling. Journal of leukocyte biology 92 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 88 31204070
2012 BTLA expression contributes to septic morbidity and mortality by inducing innate inflammatory cell dysfunction. Journal of leukocyte biology 86 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
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
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
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 69 37649037
2006 Association of Grb-2 and PI3K p85 with phosphotyrosile peptides derived from BTLA. Biochemical and biophysical research communications 68 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
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
2017 Antibodies targeting BTLA or TIM-3 enhance HIV-1 specific T cell responses in combination with PD-1 blockade. Clinical immunology (Orlando, Fla.) 52 28882621
2013 CD8 T cell memory to a viral pathogen requires trans cosignaling between HVEM and BTLA. PloS one 50 24205056
2013 BTLA interaction with HVEM expressed on CD8(+) T cells promotes survival and memory generation in response to a bacterial infection. PloS one 48 24205057
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
2016 BTLA identifies dysfunctional PD-1-expressing CD4+ T cells in human hepatocellular carcinoma. Oncoimmunology 42 28123898
2021 Combination checkpoint therapy with anti-PD-1 and anti-BTLA results in a synergistic therapeutic effect against murine glioblastoma. Oncoimmunology 41 34484870
2021 BTLA/HVEM Axis Induces NK Cell Immunosuppression and Poor Outcome in Chronic Lymphocytic Leukemia. Cancers 40 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
2006 BTLA and HVEM cross talk regulates inhibition and costimulation. Advances in immunology 39 17145304
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 The BTLA-HVEM axis restricts CAR T cell efficacy in cancer. Nature immunology 36 38831106
2022 BTLA inhibition has a dominant role in the cis-complex of BTLA and HVEM. Frontiers in immunology 36 36081508
2018 Defective BTLA functionality is rescued by restoring lipid metabolism in lupus CD4+ T cells. JCI insight 36 29997289
2018 BTLA marks a less cytotoxic T-cell subset in diffuse large B-cell lymphoma with high expression of checkpoints. Experimental hematology 35 29353075
2013 A novel nanoparticle containing MOG peptide with BTLA induces T cell tolerance and prevents multiple sclerosis. Molecular immunology 35 24084097
2024 BTLA biology in cancer: from bench discoveries to clinical potentials. Biomarker research 34 38233898
2014 An agonistic anti-BTLA mAb (3C10) induced generation of IL-10-dependent regulatory CD4+ T cells and prolongation of murine cardiac allograft. Transplantation 34 24448587
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
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
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 32 31514450
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
2024 BTLA contributes to acute-on-chronic liver failure infection and mortality through CD4+ T-cell exhaustion. Nature communications 31 38418488
2015 Cutting Edge: the BTLA-HVEM regulatory pathway interferes with protective immunity to intestinal Helminth infection. Journal of immunology (Baltimore, Md. : 1950) 31 25595777
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
2019 Divergent LAG-3 versus BTLA, TIGIT, and FCRL3 expression in Sézary syndrome. Leukemia & lymphoma 27 30638415
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 26 32296431
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 24 34709351
2012 CpG-ODN-induced sustained expression of BTLA mediating selective inhibition of human B cells. Journal of molecular medicine (Berlin, Germany) 24 22903545
2020 Disulfide-Linked Peptides for Blocking BTLA/HVEM Binding. International journal of molecular sciences 23 31963646
2024 The BTLA-HVEM complex - The future of cancer immunotherapy. European journal of medicinal chemistry 22 38387336
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
2003 Identification and disruption of btlA, a locus involved in bile tolerance and general stress resistance in Listeria monocytogenes. FEMS microbiology letters 22 12583894
2016 Association of 3' nearby gene BTLA polymorphisms with the risk of renal cell carcinoma in the Polish population. Urologic oncology 21 27234378
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 20 33017473
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 Hepatic expansion of virus-specific CD8+BTLA+ T cells with regulatory properties in chronic hepatitis B virus infection. Cellular immunology 20 27743606
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
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
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 18 33332777
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
2020 Overexpression of miR-32 inhibits the proliferation and metastasis of ovarian cancer cells by targeting BTLA. European review for medical and pharmacological sciences 16 32432730
2016 The Expression of BTLA Was Increased and the Expression of HVEM and LIGHT Were Decreased in the T Cells of Patients with Rheumatoid Arthritis [corrected]. PloS one 16 27183113
2009 Modulation of T cell proliferation through the LIGHT-HVEM-BTLA cosignaling pathway. Recent patents on DNA & gene sequences 16 19702559
2019 BTLA-HVEM Checkpoint Axis Regulates Hepatic Homeostasis and Inflammation in a ConA-Induced Hepatitis Model in Zebrafish. Journal of immunology (Baltimore, Md. : 1950) 15 31562209
2009 Cosignaling molecules around LIGHT-HVEM-BTLA: from immune activation to therapeutic targeting. Current molecular medicine 15 19860669