Affinage

TNFRSF14

Tumor necrosis factor receptor superfamily member 14 · UniProt Q92956

Length
283 aa
Mass
30.4 kDa
Annotated
2026-06-10
100 papers in source corpus 38 papers cited in narrative 38 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

TNFRSF14 (HVEM) is a TNF receptor superfamily member that operates as a bidirectional molecular switch coordinating immune signaling, mucosal defense, and tissue homeostasis (PMID:21402741, PMID:22801499, PMID:34709351). As a signaling receptor, HVEM engages the TNF-family ligand LIGHT (TNFSF14) to activate NF-κB through a C-terminal intracellular domain that recruits TRAF2 and TRAF5, driving T cell proliferation, survival, and inflammatory responses (PMID:9153189, PMID:9765287). HVEM also functions in reverse as a ligand for the Ig-superfamily receptors BTLA and CD160: in trans these engagements activate HVEM-dependent NF-κB, whereas in cis the BTLA–HVEM heterodimer on naive T cells dominantly inhibits HVEM oligomerization and signaling (PMID:19915044, PMID:36081508). Structurally, BTLA and CD160 bind the N-terminal CRD1 of HVEM—the same surface used by HSV glycoprotein D—while LIGHT occupies a distinct surface, permitting assembly of a LIGHT–HVEM–CD160 ternary complex and genetically separable TNF-ligand versus Ig-ligand functions (PMID:16169851, PMID:31230945, PMID:34709351). Through these inputs HVEM supports memory T cell persistence via Akt (PMID:21402741), drives epithelial NIK–STAT3 signaling and collagen IV synthesis to sustain intraepithelial T cells and antibacterial defense (PMID:22801499, PMID:35905286), stimulates ILC3-derived IFN-γ (PMID:30092201), and restrains germinal center B cell expansion through the BTLA–SHP1 axis (PMID:31204070). The inhibitory BTLA arm engages SHP-1/SHP-2 phosphatases, and its loss in HVEM-deficient B cells produces cell-autonomous germinal center lymphoma that is suppressed by soluble HVEM ectodomain binding BTLA (PMID:27693350, PMID:38831106). HVEM is additionally exploited by HSV: gD binding via CRD1 mediates viral entry and cell-cell fusion and blocks host ADCC responses (PMID:9223502, PMID:9621040, PMID:32817296).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1997 High

    Establishing HVEM's first identified function answered how HSV-1 enters cells, defining HVEM as a direct viral entry receptor.

    Evidence Biosensor binding and gel filtration with purified gD and HVEM plus CHO cell infection assays

    PMID:9223502

    Open questions at the time
    • Did not define the HVEM residues contacting gD
    • Cellular signaling consequences of gD binding not addressed
  2. 1997 Medium

    Identifying TRAF2/TRAF5 recruitment and NF-κB activation answered how the HVEM cytoplasmic tail transduces signals.

    Evidence Co-immunoprecipitation and NF-κB reporter assays with HVEM overexpression

    PMID:9153189

    Open questions at the time
    • Distinct roles of TRAF2 vs TRAF5 only inferred from synergy
    • No physiological ligand context in this study
  3. 1998 Medium

    Identifying LIGHT as a physiological HVEM ligand answered what TNF-family input drives HVEM signaling versus apoptosis.

    Evidence HVEM-Fc fusion competition, affinity measurement, NF-κB reporter, T cell proliferation and tumor apoptosis assays

    PMID:9739048 PMID:9765287

    Open questions at the time
    • Apoptotic versus proliferative outcome dependence on receptor co-expression (LTβR) not fully resolved
    • Single-lab affinity measurements
  4. 2001 High

    Crystal structures and truncation mapping answered where gD binds HVEM, localizing the interface to CRD1/CRD2.

    Evidence X-ray crystallography of gD–HveA complex and biosensor/ELISA with truncated HveA and blocking antibodies

    PMID:11119586 PMID:11511370

    Open questions at the time
    • Energetic contribution of individual residues not yet defined
    • Relationship to other ligand sites not addressed structurally
  5. 2000 Medium

    Competition mapping answered whether HVEM ligands share or use distinct surfaces, revealing gD, LIGHT, and LTα occupy separable sites with conformational coupling.

    Evidence Peptide and soluble receptor competition binding assays with monoclonal antibodies

    PMID:11164894

    Open questions at the time
    • Atomic basis of conformational coupling not defined
    • Ig-superfamily ligands not yet included
  6. 2002 High

    Structure-guided mutagenesis of both partners pinpointed the gD–HVEM binding hot spot (HveA-Y23, intermolecular β-sheet, CRD1 disulfide), distinguishing binding from entry determinants.

    Evidence Alanine-scanning and site-directed mutagenesis with biosensor binding and virus entry/fusion assays

    PMID:12368332 PMID:12829851

    Open questions at the time
    • Did not address how these residues influence cellular signaling
    • Generalization to immune ligands not tested
  7. 2005 High

    The BTLA–HVEM crystal structure answered how an Ig-superfamily receptor engages HVEM, showing CRD1 binding overlapping the gD site.

    Evidence X-ray crystallography, light scattering stoichiometry, alanine-scanning mutagenesis of HVEM

    PMID:16169851

    Open questions at the time
    • Functional consequence of overlap with gD site not tested here
    • Cis versus trans engagement not addressed
  8. 2008 Medium

    Functional studies answered whether gD–HVEM engagement itself signals, showing it activates NF-κB and confers anti-apoptotic protection.

    Evidence NF-κB reporter and apoptosis assays with HVEM-deficient/transfected cells, blocking antibodies, and a gD binding mutant

    PMID:18671825 PMID:18723002

    Open questions at the time
    • Downstream effectors of anti-apoptotic signaling not fully mapped
    • Single-lab findings
  9. 2009 High

    Discovery of the cis BTLA–HVEM heterodimer answered how naive T cells set their signaling baseline, defining a dominant inhibitory configuration.

    Evidence Reciprocal Co-IP, surface binding, NF-κB reporter, and BTLA-KO mice with competitive inhibition assays

    PMID:19915044

    Open questions at the time
    • Precise mechanism by which cis BTLA blocks HVEM oligomerization not structurally resolved
  10. 2011 High

    Genetic models answered how HVEM contributes to adaptive immunity, linking LIGHT–HVEM signaling to memory T cell survival via Akt and to dendritic cell homeostasis via the BTLA checkpoint.

    Evidence HVEM-KO and LIGHT-KO mice with antigen recall, Akt phosphorylation and constitutively active Akt rescue, and competitive bone marrow chimeras

    PMID:18097025 PMID:21402741

    Open questions at the time
    • Molecular link between HVEM and Akt activation not defined
    • Cell-cell directionality (T-T vs DC) requires distinct models
  11. 2012 High

    Epithelial studies answered how HVEM contributes to mucosal defense, defining a CD160–HVEM–NIK–STAT3 axis protecting against bacterial infection.

    Evidence Hvem-/- mouse infection models with STAT3 phosphorylation and CD160 ligand identification

    PMID:22801499

    Open questions at the time
    • Relative contribution of CD160 vs LIGHT in different tissues not yet dissected
  12. 2016 High

    Tumor and Treg studies answered how loss of HVEM–BTLA interactions promotes malignancy and how the pathway shapes tolerance, establishing HVEM as a B cell tumor suppressor and a CD5/Foxp3-promoting signal.

    Evidence HVEM-KO in vivo lymphoma model with solHVEM ectodomain rescue, and BTLA/HVEM-KO models tracking CD5 and Foxp3

    PMID:27693350 PMID:27793593

    Open questions at the time
    • Whether solHVEM therapy translates beyond the mouse model not addressed
    • Signaling linking HVEM engagement to CD5 upregulation not fully defined
  13. 2019 High

    Mechanistic and structural studies answered how the inhibitory arm restrains germinal centers and how CD160 engages HVEM, defining a BTLA–SHP1 cell-extrinsic brake and a CRD1-based CD160 interface.

    Evidence Conditional HVEM/BTLA deletion with immunological synapse imaging and SHP1 readout, plus X-ray crystallography of the CD160–HVEM complex

    PMID:31204070 PMID:31230945

    Open questions at the time
    • Quantitative integration of cis and trans signaling in vivo not resolved
  14. 2021 High

    The ternary complex structure plus ligand-selective knock-in mice answered whether TNF and Ig ligand arms are genetically separable, showing LIGHT-HVEM and BTLA/CD160-HVEM control distinct tissue functions.

    Evidence X-ray crystallography of LIGHT–HVEM–CD160 ternary complex with structure-based knock-in mice and infection/inflammation models

    PMID:34709351

    Open questions at the time
    • How simultaneous ligand binding modulates signaling output quantitatively not defined
  15. 2024 High

    Mechanistic dissection in CAR T cells answered how trans BTLA–HVEM engagement constrains effector function, identifying SHP-1/SHP-2 recruitment as the inhibitory output and a therapeutic target.

    Evidence CRISPR BTLA knockout in CAR T cells with phosphatase recruitment assays and in vivo tumor models

    PMID:38831106

    Open questions at the time
    • Whether HVEM-side signaling contributes to this axis in tumors not addressed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the balance between cis-inhibitory and trans-activating HVEM configurations is dynamically regulated across cell types and disease states, and how this could be therapeutically tuned, remains unresolved.
  • No structural model of the cis BTLA–HVEM heterodimer
  • Mechanism switching cells between cis and trans engagement undefined
  • Stoichiometry of signaling-competent HVEM clusters in vivo unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4 GO:0048018 receptor ligand activity 3 GO:0001618 virus receptor activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 4
Pathway
R-HSA-168256 Immune System 4 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-5357801 Programmed Cell Death 2
Partners
BTLACD160LIGHTLTAMIFTRAF2TRAF5
Complex memberships
HVEM–BTLA cis-heterodimerLIGHT–HVEM–CD160 ternary complex

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 HVEM (TNFRSF14) directly binds HSV glycoprotein D (gD) in a specific physical interaction demonstrated by biosensor and gel filtration chromatography, forming a 1:1 molar ratio complex with apparent mass of ~113 kDa; this interaction mediates HSV entry into HVEM-expressing cells and is dependent on native gD conformation but not N-linked glycosylation. Biosensor binding assay, gel filtration chromatography, CHO cell infection assay with recombinant HVEM and gD proteins Journal of virology High 9223502
1997 HVEM (ATAR) signals through TRAF2 and TRAF5 via a C-terminal 20-amino-acid intracellular domain, and overexpression of HVEM activates NF-κB; co-expression with TRAF5 (but not TRAF2) produces synergistic NF-κB activation, indicating distinct roles for these two TRAFs downstream of HVEM. Co-immunoprecipitation, NF-κB reporter assay, overexpression in cell lines The Journal of biological chemistry Medium 9153189
1998 LIGHT (TNFSF14) is a ligand for HVEM (TR2/HVEM) and induces apoptosis in tumor cells expressing both LTβR and HVEM; HVEM-Fc fusion protein specifically blocks LIGHT cytotoxicity, demonstrating direct LIGHT-HVEM interaction in cell death signaling. Receptor-Fc fusion protein competition assay, apoptosis assay in tumor cell lines The Journal of clinical investigation Medium 9739048
1998 HVEM-L (later identified as LIGHT) binds HVEM-Fc fusion protein with ~44 nM affinity and stimulates T cell proliferation and NF-κB-dependent transcription through HVEM, as shown by binding specificity assays with soluble and membrane forms. HVEM-Fc fusion protein binding screen, NF-κB reporter assay, T cell proliferation assay The Journal of biological chemistry Medium 9765287
1998 HveA (HVEM) mediates HSV-1-induced cell-cell fusion as well as free virus entry; antibodies against gD and HveA block syncytium formation, and the form of virally expressed gD determines whether HveA can mediate fusion, linking gD-HveA interaction to both entry and fusion. CHO-HveA cell transfection, syncytium assay, antibody blocking Journal of virology Medium 9621040
2001 X-ray crystal structure of HSV-1 gD ectodomain bound to HveA (HVEM) ectodomain reveals that the gD N-terminal hairpin contacts CRD1 of HVEM, forming a specific binding interface; two anions suggest possible binding sites for 3-O-sulfonated heparan sulfate receptor. X-ray crystallography of gD alone and gD–HveA complex Molecular cell High 11511370
2001 The gD-binding domain of HveA resides within CRD1 and CRD2 (residues 1–120); CRD1 alone (HveA(76t)) is insufficient for gD binding, and the monoclonal antibody CW3, which blocks a discontinuous epitope in CRD1, inhibits gD binding and virus entry. Biosensor assay, ELISA, virus entry blocking assay with truncated HveA proteins and monoclonal antibodies Journal of virology High 11119586
2000 gD, LIGHT, and LT-α each bind to distinct sites on HveA (HVEM), as shown by peptide competition assays differentially blocking each ligand; binding of one ligand can alter the conformation of HveA, potentially affecting interaction with other ligands. Competition binding assay with peptide ligands, soluble receptor forms, and monoclonal antibodies Molecular immunology Medium 11164894
2002 Structure-based alanine-scanning mutagenesis of HveA identifies a binding hot spot centered on HveA-Y23, which protrudes into a crevice on gD; an intermolecular β-sheet between gD and HveA residues 35–37 contributes to binding, and the C37–C19 disulfide bond in CRD1 is critical for gD binding. CRD2 provides structural support rather than direct contact energy. Site-directed mutagenesis, biosensor binding assay, virus entry assay, oligomerization analysis Journal of virology High 12368332
2003 Structure-based mutagenesis of gD defines three critical regions at the gD-HveA interface: (i) residues forming an intermolecular β-sheet with HveA are crucial for binding and entry; (ii) residues contacting HveA-Y23 contribute to binding but not entry; (iii) one gD residue contacts CRD2 and contributes to binding. Site-directed mutagenesis, receptor-binding assay, virus entry assay, cell-cell fusion assay Journal of virology High 12829851
2005 2.8-Å crystal structure of the BTLA–HVEM complex shows BTLA binds the N-terminal CRD1 of HVEM using a surface that overlaps with the gD binding site and employs a similar binding motif. BTLA is monomeric and forms a 1:1 complex with HVEM. Alanine-scanning mutagenesis of HVEM defines critical binding residues. X-ray crystallography, light scattering, alanine-scanning mutagenesis of HVEM The Journal of biological chemistry High 16169851
2008 HVEM-dependent NF-κB activation by HSV-1 gD is mediated through the gD–HVEM interaction: UV-inactivated HSV-1 or soluble gD activates NF-κB only in HVEM-expressing cells; antibodies blocking gD–HVEM binding reduce NF-κB activation; a gD mutant unable to bind HVEM fails to activate NF-κB. NF-κB reporter assay, antibody blocking, HVEM-transfected and HVEM-deficient cell lines, gD binding mutant Cellular microbiology Medium 18671825
2008 gD–HVEM interaction mediates NF-κB-dependent protection against Fas- and staurosporine-induced apoptosis; antibodies blocking gD–HVEM binding reduce this anti-apoptotic effect, and a gD mutant that cannot bind HVEM fails to protect cells. Apoptosis assay (anti-Fas, staurosporine), antibody blocking, gD binding mutant in HVEM-expressing cells Biochemical pharmacology Medium 18723002
2009 BTLA and HVEM form a cis-heterodimeric complex on the surface of naive T cells that inhibits HVEM-dependent NF-κB activation; BTLA ectodomain competitively inhibits trans engagement of BTLA and CD160 with HVEM; LIGHT binds the cis-complex but NF-κB activation is attenuated, suggesting BTLA prevents HVEM oligomerization; genetic deletion of BTLA or pharmacologic disruption of the cis-complex promotes HVEM activation in trans. Co-immunoprecipitation, cell surface binding assay, NF-κB reporter assay, BTLA-KO mice, competitive inhibition assay Journal of immunology High 19915044
2011 HVEM-deficient memory CD4 T cells (Th2 and Th1) fail to persist after recall antigen encounter, displaying reduced PKB/Akt activity; constitutively active Akt rescues survival of HVEM-deficient Th2 memory cells. LIGHT-deficient T cells recapitulate the HVEM-deficient defect, indicating LIGHT-HVEM T cell–T cell interactions are required for memory T cell persistence. HVEM-KO and LIGHT-KO mouse models, antigen recall assay, Akt phosphorylation assay, constitutively active Akt rescue The Journal of experimental medicine High 21402741
2012 Epithelial HVEM promotes host defense against intestinal Citrobacter rodentium and pulmonary Streptococcus pneumoniae infection by activating NF-κB-inducing kinase–dependent STAT3 signaling in epithelial cells; CD160 expressed by innate-like intraepithelial lymphocytes is the ligand that engages epithelial HVEM for this protective signaling. Hvem-/- mouse infection model, STAT3 phosphorylation assay, CD160 identification as HVEM ligand, gene expression analysis Nature High 22801499
2016 Loss of HVEM (TNFRSF14) causes cell-autonomous B cell proliferation and GC lymphoma development in vivo; HVEM-deficient lymphoma B cells disrupt inhibitory HVEM–BTLA cell–cell contacts, leading to exacerbated lymphoid stroma activation and increased TFH cell recruitment; administration of solHVEM(P37-V202) binds BTLA and restores tumor suppression in vivo. HVEM-KO in vivo lymphoma model, B cell proliferation assay, tumor microenvironment analysis, solHVEM ectodomain treatment, BTLA binding assay Cell High 27693350
2019 HVEM on B cells restrains T helper signals delivered to B cells in germinal centers through a cell-extrinsic mechanism: BTLA on T cells signals via the phosphatase SHP1 to reduce TCR signaling and preformed CD40L mobilization to the immunological synapse, diminishing help to HVEM-expressing B cells; T cell BTLA deficiency combined with B cell Bcl-2 overexpression leads to GC B cell outgrowth. Genetic deletion of HVEM on B cells, BTLA KO T cells, imaging of immunological synapse (CD40L mobilization), mixed bone marrow chimeras, Bcl-2 transgenic mice Immunity High 31204070
2019 Crystal structure of the CD160–HVEM complex at 2.x Å reveals CD160 adopts a unique Ig fold variant and engages HVEM in a 1:1 complex at a binding interface similar to the BTLA–HVEM interface (CRD1 region), establishing the structural basis for CD160–HVEM bidirectional signaling. X-ray crystallography, light scattering (stoichiometry determination) Structure High 31230945
2021 Crystal structures reveal that LIGHT and BTLA/CD160 bind to distinct surfaces on HVEM; a human HVEM–LIGHT–CD160 ternary complex structure demonstrates simultaneous binding of both partners. Structure-guided HVEM knock-in mutants selectively recognizing either TNF or Ig ligands in mice show that LIGHT-HVEM signaling is selectively required for bacterial clearance in the intestine, while Ig ligand (BTLA/CD160)–HVEM signaling is selectively required for amelioration of liver inflammation. X-ray crystallography (ternary complex), structure-based mutagenesis, knock-in mouse models, bacterial infection model, liver inflammation model The Journal of experimental medicine High 34709351
2018 HVEM signaling in LIGHT-mediated ILC3 activation is required for host defense against Yersinia enterocolitica; LIGHT is the ligand inducing HVEM signals in ILC3 that stimulate protective IFN-γ secretion; adoptive transfer of wild-type but not IFN-γ-deficient ILC3 restores protection in ILC-deficient mice. HVEM-conditional KO (ILC3-specific), adoptive transfer, IFN-γ production assay, bacterial infection model Cell host & microbe High 30092201
2018 HVEM expressed in keratinocytes mediates LIGHT-driven keratinocyte hyperplasia and periostin expression; keratinocyte-specific HVEM deletion or antibody blocking of LIGHT-HVEM reduces epidermal thickening, collagen deposition, and periostin in a house dust mite model of atopic dermatitis; LIGHT directly induces keratinocyte proliferation and periostin through HVEM in human epidermal keratinocytes. Keratinocyte-conditional HVEM KO mice, antibody blockade of LIGHT-HVEM, atopic dermatitis model, human keratinocyte culture with LIGHT stimulation The Journal of experimental medicine High 29339444
2016 TNFRSF14 (HVEM) expression on mast cells mediates TNFSF14 (LIGHT)-enhanced IgE-mediated mast cell signaling and mediator production; reconstitution of MC-deficient mice with TNFRSF14-expressing (but not TNFRSF14-deficient) mast cells restores multiple asthma pathology features including airway hyperreactivity, inflammation, and remodeling. Tnfrsf14-KO mice, mast-cell-deficient mouse reconstitution with TNFRSF14+/+ vs TNFRSF14-/- MCs, antibody neutralization, IgE signaling assay Nature communications High 27982078
2011 HVEM-BTLA pathway controls homeostasis of CD8α- dendritic cell subsets in the spleen; HVEM- or BTLA-deficient DCs show a specific growth advantage in repopulating the spleen in competitive bone marrow chimeras; DC expression of both HVEM and BTLA is required, and LTβR drives DC expansion that is counter-regulated by the HVEM-BTLA inhibitory checkpoint. HVEM-KO and BTLA-KO mice, competitive bone marrow chimera, flow cytometry of DC subsets, LTβR agonist treatment Journal of immunology High 18097025
2016 BTLA expressed on DEC205+CD8+CD11c+ DCs promotes extrathymic Treg induction; HVEM engagement on T cells upregulates CD5, which in turn enables Foxp3 expression by resisting effector-cytokine-mediated suppression of Foxp3; T cells activated in the absence of BTLA-HVEM signaling remain CD5lo and fail to sustain Foxp3. BTLA-KO DC transfer, HVEM-KO T cells, CD5 expression analysis, Foxp3 reporter, cytokine stimulation assay Immunity High 27793593
2005 LIGHT-HVEM interaction enhances bactericidal activity against Listeria monocytogenes and Staphylococcus aureus in monocytes and neutrophils by increasing phagocytosis, IL-8, TNF-α, nitric oxide, and ROS; anti-HVEM monoclonal antibody blocks all these effects, and ROS/NO inhibition abrogates LIGHT-HVEM-driven bactericidal activity. Anti-HVEM antibody blockade, ROS/NO inhibitors, cytokine ELISA, bactericidal assay Journal of leukocyte biology Medium 16275888
2011 LIGHT (sLIGHT) enhances adipose tissue inflammatory responses (macrophage chemotaxis, cytokine release) through HVEM; neutralizing anti-HVEM antibody or HVEM knockout abolishes sLIGHT-induced inflammatory responses in macrophages, adipocytes, and SVF cells. Anti-HVEM neutralizing antibody, HVEM-KO cells/mice, chemotaxis assay, cytokine ELISA FEBS letters Medium 21236258
2013 HVEM promotes CD4+ T cell survival during Strongyloides ratti infection through BTLA engagement; HVEM or BTLA deficiency reduces parasite burden via accelerated mast cell degranulation and increased IL-9 production, placing HVEM upstream of BTLA-mediated suppression of the anti-helminth response. HVEM-KO and BTLA-KO mice, parasite infection model, mast cell degranulation assay, IL-9 measurement Journal of immunology Medium 25595777
2013 BTLA expressed on CD8α+ dendritic cells acts as a trans-activating ligand that delivers positive co-signals through HVEM on T cells to promote CD8 T cell memory formation after vaccinia virus infection; mixed adoptive transfer experiments established the trans (DC-to-T cell) direction of this signaling. HVEM-KO and BTLA-KO mice, vaccinia virus infection, mixed adoptive transfer, memory CD8 T cell quantification PloS one Medium 24205056
2011 BTLA expressed on donor T cells serves a dual role in GVHD: (1) as a receptor transmitting inhibitory signals that suppress anti-host T cell responses; and (2) as a ligand that delivers HVEM pro-survival signals to donor T cells, demonstrated using a BTLA mutant lacking the intracellular signaling domain that rescues impaired T cell survival without transmitting inhibitory signals. Agonistic anti-BTLA antibody, BTLA intracellular domain deletion mutant, GVHD mouse model, donor T cell survival assay Blood Medium 21220749
2023 MIF (Macrophage Migration Inhibitory Factor) directly binds HVEM and activates NF-κB signaling to promote Th17 cell differentiation; anti-HVEM antibody blockade abolishes MIF-induced Th17 differentiation, establishing HVEM as the receptor mediating MIF's effect. Direct binding assay (MIF–HVEM), anti-HVEM antibody blockade, NF-κB phosphorylation assay, Th17 differentiation assay International immunopharmacology Medium 37331297
2022 In cis, BTLA co-expression with HVEM results in dominant BTLA-mediated inhibition rather than HVEM co-stimulation; LIGHT and CD160 (but not BTLA) co-expression with HVEM induces constitutive HVEM signaling; HVEM antibodies can simultaneously act as checkpoint inhibitors and co-stimulation agonists on primary human T cells. T cell reporter system, primary human T cell stimulation, HVEM ligand co-expression constructs, NF-κB and NFAT reporter readouts Frontiers in immunology Medium 36081508
2024 BTLA on effector CAR T cells inhibits antitumor function by recruiting tyrosine phosphatases SHP-1 and SHP-2 upon trans engagement with HVEM 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. CRISPR BTLA knockout in CAR T cells, SHP-1/SHP-2 recruitment assay, in vivo tumor models (lymphoma, solid tumors), clinical correlation with CAR T response Nature immunology High 38831106
2020 HVEM signaling is required for generating ADCC-mediating IgG2 antibodies after HSV vaccination; Hvem-/- mice produce fewer HSV-specific IgG2 antibodies with reduced ADCC titers and impaired FcγR activation; addition of gD protein or anti-HVEM antibodies to in vitro FcγR activation assays inhibits the response, showing gD–HVEM engagement by HSV blocks host ADCC responses. Hvem-/- mouse vaccination, passive serum transfer, in vitro FcγR activation assay, antibody isotyping Science immunology High 32817296
2022 Epithelial HVEM promotes survival of small intestine intraepithelial T cells (IETs) at steady state by inducing epithelial synthesis of basement membrane protein collagen IV, which engages β1 integrins on IETs; intravital microscopy shows HVEM-deficient epithelium reduces IET patrolling movement; β1 integrin–collagen IV interactions are required for IET maintenance and protective responses to Salmonella. HVEM conditional KO in epithelium, RNA-seq of organoids, β1 integrin-KO T cells, collagen IV measurement, intravital microscopy, Salmonella infection model Science immunology High 35905286
2013 HVEM expression is upregulated in neurons during HSV-1 latency by the viral latency-associated transcript (LAT); LAT upregulates HVEM expression in vivo and in vitro in the absence of other viral factors; HSV-1 latency/reactivation is significantly reduced in Hvem-/- mice, indicating HVEM promotes latency establishment and reactivation. Hvem-/- mouse latency model, LAT expression constructs, in vivo and in vitro HVEM expression measurement, viral latency quantification Journal of virology Medium 24307582
2009 LIGHT stimulation through HVEM (but not LTβR) induces upregulation of apoptotic genes and CLL cell death, activation of caspases, loss of mitochondrial membrane potential, upregulation of Bax, and TRAIL involvement; HVEM stimulation also induces endogenous TNF-α production which enhances HVEM-mediated cell death. Other HVEM ligands (gD, BTLA) are largely ineffective in this killing pathway. Anti-HVEM mAb stimulation, LIGHT treatment, caspase activation assay, mitochondrial membrane potential measurement, Bax immunoblot, TNF-α ELISA, receptor-specific blocking European journal of immunology Medium 19701890
2013 TNFRSF14 deficiency in ovariectomized mice attenuates adipose tissue inflammation by reducing CD11c+ macrophage recruitment and polarization to M1; LIGHT engagement of TNFRSF14 (HVEM) enhances CD11c expression via ROS generation, identifying HVEM as a redox modulator in adipose tissue inflammatory signaling. Tnfrsf14-KO mouse ovariectomy model, flow cytometry of CD11c+ cells, ROS measurement, bone marrow-derived macrophage polarization assay The Journal of endocrinology Medium 24287621

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 Herpes simplex virus glycoprotein D bound to the human receptor HveA. Molecular cell 319 11511370
2006 Balancing co-stimulation and inhibition with BTLA and HVEM. Nature reviews. Immunology 258 16932752
1997 Glycoprotein D of herpes simplex virus (HSV) binds directly to HVEM, a member of the tumor necrosis factor receptor superfamily and a mediator of HSV entry. Journal of virology 255 9223502
2009 The CD160, BTLA, LIGHT/HVEM pathway: a bidirectional switch regulating T-cell activation. Immunological reviews 247 19426226
1998 LIGHT, a novel ligand for lymphotoxin beta receptor and TR2/HVEM induces apoptosis and suppresses in vivo tumor formation via gene transfer. The Journal of clinical investigation 211 9739048
2016 Loss of the HVEM Tumor Suppressor in Lymphoma and Restoration by Modified CAR-T Cells. Cell 207 27693350
2011 The signaling networks of the herpesvirus entry mediator (TNFRSF14) in immune regulation. Immunological reviews 199 22017438
1998 Herpesvirus entry mediator ligand (HVEM-L), a novel ligand for HVEM/TR2, stimulates proliferation of T cells and inhibits HT29 cell growth. The Journal of biological chemistry 193 9765287
2010 Slow down and survive: Enigmatic immunoregulation by BTLA and HVEM. Annual review of immunology 188 20307212
1997 ATAR, a novel tumor necrosis factor receptor family member, signals through TRAF2 and TRAF5. The Journal of biological chemistry 148 9153189
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
2016 Immunomodulatory Functions of BTLA and HVEM Govern Induction of Extrathymic Regulatory T Cells and Tolerance by Dendritic Cells. Immunity 122 27793593
2012 HVEM signalling at mucosal barriers provides host defence against pathogenic bacteria. Nature 119 22801499
2008 A crucial role for HVEM and BTLA in preventing intestinal inflammation. The Journal of experimental medicine 116 18519647
2003 LIGHT-HVEM signaling and the regulation of T cell-mediated immunity. Cytokine & growth factor reviews 109 12787566
2016 Genome-wide analysis of pediatric-type follicular lymphoma reveals low genetic complexity and recurrent alterations of TNFRSF14 gene. Blood 105 27257180
2003 Structure-based mutagenesis of herpes simplex virus glycoprotein D defines three critical regions at the gD-HveA/HVEM binding interface. Journal of virology 103 12829851
2003 Mutations in the N termini of herpes simplex virus type 1 and 2 gDs alter functional interactions with the entry/fusion receptors HVEM, nectin-2, and 3-O-sulfated heparan sulfate but not with nectin-1. Journal of virology 98 12915538
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
2002 Modulation of LIGHT-HVEM costimulation prolongs cardiac allograft survival. The Journal of experimental medicine 90 11901205
2002 Structure-based analysis of the herpes simplex virus glycoprotein D binding site present on herpesvirus entry mediator HveA (HVEM). Journal of virology 90 12368332
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
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
1998 HveA (herpesvirus entry mediator A), a coreceptor for herpes simplex virus entry, also participates in virus-induced cell fusion. Journal of virology 71 9621040
2019 BTLA/HVEM Signaling: Milestones in Research and Role in Chronic Hepatitis B Virus Infection. Frontiers in immunology 70 30984188
2008 HVEM and nectin-1 are the major mediators of herpes simplex virus 1 (HSV-1) entry into human conjunctival epithelium. Investigative ophthalmology & visual science 67 18502984
2011 Herpesvirus entry mediator (TNFRSF14) regulates the persistence of T helper memory cell populations. The Journal of experimental medicine 62 21402741
2013 Interfering with coinhibitory molecules: BTLA/HVEM as new targets to enhance anti-tumor immunity. Immunology letters 60 23439006
2012 The HVEM network: new directions in targeting novel costimulatory/co-inhibitory molecules for cancer therapy. Current opinion in pharmacology 59 22445654
2006 Selective targeting of the LIGHT-HVEM costimulatory system for the treatment of graft-versus-host disease. Blood 58 17179227
2005 LIGHT enhances the bactericidal activity of human monocytes and neutrophils via HVEM. Journal of leukocyte biology 58 16275888
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
2016 Characterization of a variant of t(14;18) negative nodal diffuse follicular lymphoma with CD23 expression, 1p36/TNFRSF14 abnormalities, and STAT6 mutations. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 54 26965583
2013 Recurrent loss of heterozygosity in 1p36 associated with TNFRSF14 mutations in IRF4 translocation negative pediatric follicular lymphomas. Haematologica 53 23445872
2013 CD8 T cell memory to a viral pathogen requires trans cosignaling between HVEM and BTLA. PloS one 50 24205056
2018 LIGHT-HVEM Signaling in Innate Lymphoid Cell Subsets Protects Against Enteric Bacterial Infection. Cell host & microbe 49 30092201
2001 Localization of the gD-binding region of the human herpes simplex virus receptor, HveA. Journal of virology 47 11119586
2009 Targeting the LIGHT-HVEM pathway. Advances in experimental medicine and biology 45 19760072
2005 Proinflammatory effects of LIGHT through HVEM and LTbetaR interactions in cultured human umbilical vein endothelial cells. Journal of biomedical science 45 15917993
2019 HVEM network signaling in cancer. Advances in cancer research 44 30885361
2013 Interactions between herpesvirus entry mediator (TNFRSF14) and latency-associated transcript during herpes simplex virus 1 latency. Journal of virology 44 24307582
2011 Dichotomous regulation of GVHD through bidirectional functions of the BTLA-HVEM pathway. Blood 44 21220749
1993 HVEM ultrastructural analysis of mouse fungiform taste buds, cell types, and associated synapses. Microscopy research and technique 44 8241550
2008 Involvement of HVEM receptor in activation of nuclear factor kappaB by herpes simplex virus 1 glycoprotein D. Cellular microbiology 43 18671825
2019 Mechanism of regulation and neutralization of the AtaR-AtaT toxin-antitoxin system. Nature chemical biology 42 30718814
2018 The immune checkpoint, HVEM may contribute to immune escape in non-small cell lung cancer lacking PD-L1 expression. Lung cancer (Amsterdam, Netherlands) 40 30429008
2008 Involvement of gD/HVEM interaction in NF-kB-dependent inhibition of apoptosis by HSV-1 gD. Biochemical pharmacology 40 18723002
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
2024 The BTLA-HVEM axis restricts CAR T cell efficacy in cancer. Nature immunology 38 38831106
2018 LIGHT-HVEM signaling in keratinocytes controls development of dermatitis. The Journal of experimental medicine 38 29339444
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
2017 Expression and Clinical Significance of Herpes Virus Entry Mediator (HVEM) in Breast Cancer. Annals of surgical oncology 37 28612127
2022 BTLA inhibition has a dominant role in the cis-complex of BTLA and HVEM. Frontiers in immunology 36 36081508
2000 The three HveA receptor ligands, gD, LT-alpha and LIGHT bind to distinct sites on HveA. Molecular immunology 36 11164894
2019 Structural Basis of CD160:HVEM Recognition. Structure (London, England : 1993) 35 31230945
2011 LIGHT/TNFSF14 enhances adipose tissue inflammatory responses through its interaction with HVEM. FEBS letters 35 21236258
2003 Stimulation of non-Hodgkin's lymphoma via HVEM: an alternate and safe way to increase Fas-induced apoptosis and improve tumor immunogenicity. Leukemia 35 14562115
2016 A TNFRSF14-FcɛRI-mast cell pathway contributes to development of multiple features of asthma pathology in mice. Nature communications 34 27982078
2015 Cutting Edge: the BTLA-HVEM regulatory pathway interferes with protective immunity to intestinal Helminth infection. Journal of immunology (Baltimore, Md. : 1950) 33 25595777
2012 A herpes simplex virus 2 glycoprotein D mutant generated by bacterial artificial chromosome mutagenesis is severely impaired for infecting neuronal cells and infects only Vero cells expressing exogenous HVEM. Journal of virology 33 22993162
2009 Regulating the mucosal immune system: the contrasting roles of LIGHT, HVEM, and their various partners. Seminars in immunopathology 33 19495760
2009 A role for HVEM, but not lymphotoxin-beta receptor, in LIGHT-induced tumor cell death and chemokine production. European journal of immunology 33 19701890
2009 Generation of herpesvirus entry mediator (HVEM)-restricted herpes simplex virus type 1 mutant viruses: resistance of HVEM-expressing cells and identification of mutations that rescue nectin-1 recognition. Journal of virology 32 19129446
2012 Low herpesvirus entry mediator (HVEM) expression on dermal fibroblasts contributes to a Th2-dominant microenvironment in advanced cutaneous T-cell lymphoma. The Journal of investigative dermatology 30 22297640
2016 TNFRSF14 aberrations in follicular lymphoma increase clinically significant allogeneic T-cell responses. Blood 29 27103745
2017 Design of short peptides to block BTLA/HVEM interactions for promoting anticancer T-cell responses. PloS one 28 28594868
2012 Herpes B virus utilizes human nectin-1 but not HVEM or PILRα for cell-cell fusion and virus entry. Journal of virology 28 22345445
2002 Crystallization and preliminary diffraction studies of the ectodomain of the envelope glycoprotein D from herpes simplex virus 1 alone and in complex with the ectodomain of the human receptor HveA. Acta crystallographica. Section D, Biological crystallography 28 11976496
1986 The synaptic ultrastructure in the outer plexiform layer of the catfish retina: a three-dimensional study with HVEM and conventional EM of Golgi-impregnated bipolar and horizontal cells. The Journal of comparative neurology 28 2424939
2022 Epithelial HVEM maintains intraepithelial T cell survival and contributes to host protection. Science immunology 27 35905286
2021 Blockade of HVEM for Prostate Cancer Immunotherapy in Humanized Mice. Cancers 27 34208480
2009 Role of nectin-1, HVEM, and PILR-alpha in HSV-2 entry into human retinal pigment epithelial cells. Investigative ophthalmology & visual science 27 19234349
2007 Blockade of LIGHT/HVEM and B7/CD28 signaling facilitates long-term islet graft survival with development of allospecific tolerance. Transplantation 27 17893608
2017 Monoclonal Antibodies, Derived from Humans Vaccinated with the RV144 HIV Vaccine Containing the HVEM Binding Domain of Herpes Simplex Virus (HSV) Glycoprotein D, Neutralize HSV Infection, Mediate Antibody-Dependent Cellular Cytotoxicity, and Protect Mice from Ocular Challenge with HSV-1. Journal of virology 26 28701403
2014 HVEM is a TNF Receptor with Multiple Regulatory Roles in the Mucosal Immune System. Immune network 26 24851095
2013 HVEM: An unusual TNF receptor family member important for mucosal innate immune responses to microbes. Gut microbes 26 23333859
2021 Frequent mutated B2M, EZH2, IRF8, and TNFRSF14 in primary bone diffuse large B-cell lymphoma reflect a GCB phenotype. Blood advances 25 34478526
2021 HVEM structures and mutants reveal distinct functions of binding to LIGHT and BTLA/CD160. The Journal of experimental medicine 25 34709351
2013 LIGHT/HVEM/LTβR interaction as a target for the modulation of the allogeneic immune response in transplantation. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 25 23356438
2008 An 18-week, prospective, randomized, double-blind, multicenter study of amlodipine/ramipril combination versus amlodipine monotherapy in the treatment of hypertension: the assessment of combination therapy of amlodipine/ramipril (ATAR) study. Clinical therapeutics 25 18840367
2005 Lymphtoxin beta receptor-Ig ameliorates TNBS-induced colitis via blocking LIGHT/HVEM signaling. Pharmacological research 25 15925518
2016 Knockdown of HVEM, a Lymphocyte Regulator Gene, in Ovarian Cancer Cells Increases Sensitivity to Activated T Cells. Oncology research 24 27458100
1998 Herpesvirus entry mediator HVEM mediates cell-cell spread in BHK(TK-) cell clones. Journal of virology 24 9445042
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
2018 Concomitant 1p36 deletion and TNFRSF14 mutations in primary cutaneous follicle center lymphoma frequently expressing high levels of EZH2 protein. Virchows Archiv : an international journal of pathology 23 29858685
2015 Recurrent somatic loss of TNFRSF14 in classical Hodgkin lymphoma. Genes, chromosomes & cancer 23 26650888
1999 Functional characterization of the HveA homolog specified by African green monkey kidney cells with a herpes simplex virus expressing the green fluorescence protein. Virology 23 10366573
2020 HVEM signaling promotes protective antibody-dependent cellular cytotoxicity (ADCC) vaccine responses to herpes simplex viruses. Science immunology 22 32817296
2023 MIF promotes Th17 cell differentiation in Hashimoto's thyroiditis by binding HVEM and activating NF-κB signaling pathway. International immunopharmacology 21 37331297
2017 Murine Corneal Inflammation and Nerve Damage After Infection With HSV-1 Are Promoted by HVEM and Ameliorated by Immune-Modifying Nanoparticle Therapy. Investigative ophthalmology & visual science 21 28114589
2013 TNFRSF14 deficiency protects against ovariectomy-induced adipose tissue inflammation. The Journal of endocrinology 21 24287621
2009 Expression of herpes virus entry mediator (HVEM) in the cornea and trigeminal ganglia of normal and HSV-1 infected mice. Current eye research 21 19895317
2006 Prevention of the interaction between HVEM, herpes virus entry mediator, and gD, HSV envelope protein, by a Keggin polyoxotungstate, PM-19. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 21 16675194
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

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