Affinage

TNFRSF14

Tumor necrosis factor receptor superfamily member 14 · UniProt Q92956

Length
283 aa
Mass
30.4 kDa
Annotated
2026-04-28
100 papers in source corpus 27 papers cited in narrative 27 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TNFRSF14 (HVEM) is a bidirectional signaling hub at the interface of the TNF receptor and immunoglobulin superfamilies, integrating pro-inflammatory, survival, and inhibitory signals to regulate lymphocyte activation, memory, tolerance, and mucosal immunity. Its CRD1 domain engages Ig-superfamily ligands BTLA and CD160 (and HSV glycoprotein D) to deliver inhibitory signals via SHP-1/SHP-2 recruitment on the opposing cell, while a distinct surface binds TNF-family ligands LIGHT and LTα to activate NF-κB (through TRAF2/TRAF5), STAT3, and Akt survival pathways (PMID:9153189, PMID:34709351, PMID:20307212, PMID:21402741). On naive T cells, HVEM and BTLA form a cis-complex that competitively blocks trans-engagement, maintaining inhibitory tone; disruption of this complex releases B and T cell activation and, in germinal center B cells, promotes lymphomagenesis driven by unchecked TFH help (PMID:19915044, PMID:27693350, PMID:31204070). In mucosal tissues, LIGHT–HVEM signaling on ILC3 drives protective IFN-γ during enteric infection, while epithelial HVEM stimulates collagen IV production that sustains intraepithelial T cell survival through β1 integrins (PMID:30092201, PMID:35905286).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1997 High

    Identification of HVEM as the entry receptor for HSV via direct binding of glycoprotein D established that a TNF receptor family member could serve as a viral receptor, opening investigation of its ligand repertoire.

    Evidence Recombinant protein binding assays, gel filtration, and CHO cell infection assays

    PMID:9223502

    Open questions at the time
    • Physiological (non-viral) ligands were unknown
    • Signaling consequences of gD engagement were uncharacterized
  2. 1997 High

    Demonstration that HVEM signals through TRAF2 and TRAF5 to activate NF-κB revealed that HVEM functions as a classical TNFR-family signaling receptor, not merely a viral entry factor.

    Evidence Yeast two-hybrid, co-immunoprecipitation, NF-κB reporter assay with domain mapping

    PMID:9153189

    Open questions at the time
    • Identity of endogenous activating ligands was unknown
    • Downstream transcriptional targets of HVEM-NF-κB not defined
  3. 2000 Medium

    Competitive binding studies showed that gD, LTα, and LIGHT occupy distinct but overlapping sites on HVEM, establishing that HVEM is a multi-ligand receptor capable of integrating different inputs.

    Evidence Competitive binding assays with recombinant HVEM truncation mutants and peptide inhibitors

    PMID:11164894

    Open questions at the time
    • Structural basis for distinct binding faces not resolved
    • Functional consequence of simultaneous ligand engagement unknown
  4. 2001 High

    Crystal structures of gD alone and in complex with HVEM, combined with domain mapping, localized the gD contact to CRD1 and revealed a conformational change mechanism relevant to viral entry.

    Evidence X-ray crystallography at atomic resolution; biosensor binding and antibody blocking with HVEM truncation mutants

    PMID:11119586 PMID:11511370 PMID:12368332

    Open questions at the time
    • Whether CRD1 also served as the binding site for endogenous Ig-superfamily ligands was unknown
    • Structural basis for LIGHT/LTα binding not yet determined
  5. 2005 High

    The crystal structure of the BTLA–HVEM complex revealed that an Ig-superfamily inhibitory receptor binds CRD1 of a TNF receptor, using a surface overlapping with gD, establishing an unprecedented cross-superfamily signaling paradigm.

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

    PMID:16169851

    Open questions at the time
    • How BTLA inhibitory signaling was transduced upon HVEM engagement was incompletely defined
    • Whether CD160 shared this binding mode was unknown
  6. 2008 High

    In vivo genetic studies demonstrated that HVEM–BTLA signaling functions as an inhibitory checkpoint controlling dendritic cell homeostasis and preventing intestinal inflammation, establishing HVEM's physiological role as a negative regulator beyond T cells.

    Evidence HVEM-KO and BTLA-KO mice, competitive bone marrow chimeras, T cell transfer colitis model

    PMID:18097025 PMID:18519647

    Open questions at the time
    • Cell-type-specific contributions of HVEM in epithelium vs. immune compartment were not separated
    • STAT3 pathway involvement not yet established
  7. 2008 High

    gD–HVEM engagement was shown to activate NF-κB-dependent anti-apoptotic signaling, demonstrating that HSV exploits HVEM survival signaling during infection.

    Evidence Blocking MAbs, non-binding gD mutants, Fas-mediated apoptosis assays in HVEM-expressing cells

    PMID:18723002

    Open questions at the time
    • Whether this survival pathway operates during latency was unresolved
    • Downstream NF-κB target genes not identified
  8. 2009 High

    Discovery that BTLA and HVEM form a cis-complex on naive T cells that blocks trans-activation resolved how inhibitory tone is maintained at steady state and explained why HVEM loss leads to immune activation.

    Evidence Co-immunoprecipitation, NF-κB reporter assays, FACS-based binding, genetic deletion in T cells

    PMID:19915044

    Open questions at the time
    • Molecular mechanism preventing HVEM oligomerization in cis not fully resolved
    • How the cis-complex is disrupted during activation was not defined
  9. 2010 Medium

    Characterization of HVEM–BTLA as a bidirectional signaling axis — BTLA delivers SHP-1/SHP-2 inhibitory signals while HVEM receives NF-κB-activating signals — unified the co-stimulatory and co-inhibitory functions into a single molecular interaction.

    Evidence Biochemical signaling assays, co-immunoprecipitation (synthesized from multiple primary studies)

    PMID:20307212

    Open questions at the time
    • Relative contribution of SHP-1 vs. SHP-2 in different cell types not delineated
    • Quantitative signaling thresholds not established
  10. 2011 High

    HVEM was shown to promote memory T cell persistence through Akt survival signaling triggered by LIGHT, identifying a non-redundant role for HVEM in adaptive immune memory maintenance.

    Evidence HVEM-KO and LIGHT-KO memory CD4 T cell transfers, Akt phosphorylation assays, constitutively active Akt rescue

    PMID:21402741

    Open questions at the time
    • Whether Akt activation is TRAF-dependent or uses a distinct adaptor was unknown
    • Role in CD8 memory maintenance not fully tested
  11. 2013 Medium

    HSV-1 latency-associated transcript was found to upregulate HVEM expression in neurons, and HVEM-deficient mice showed reduced latency and reactivation, revealing that HSV co-opts HVEM signaling for long-term persistence.

    Evidence Hvem−/− mouse latency model, LAT noncoding RNA promoter-binding studies

    PMID:24307582

    Open questions at the time
    • LAT–HVEM promoter interaction not validated by independent lab
    • Downstream neuronal survival pathway not fully delineated
  12. 2016 High

    Loss of HVEM in germinal center B cells was shown to drive cell-autonomous proliferation and lymphomagenesis; soluble HVEM ectodomain restored BTLA-dependent tumor suppression, establishing HVEM as a tumor suppressor in GC B cell lymphoma.

    Evidence In vivo mouse lymphoma model, HVEM-KO B cell adoptive transfer, solHVEM protein rescue, CAR-T engineering

    PMID:27693350

    Open questions at the time
    • Whether solHVEM achieves durable suppression in established tumors was not tested
    • Downstream transcriptional program in HVEM-deficient GC B cells not characterized
  13. 2016 High

    Multiple tissue-specific roles of HVEM were simultaneously uncovered: BTLA-expressing DCs use HVEM engagement to upregulate CD5 and induce Foxp3+ regulatory T cells; HVEM on mast cells mediates LIGHT-driven IgE signaling and asthma pathology; and SALM5 was identified as a neuronal HVEM ligand suppressing CNS inflammation.

    Evidence DC subset analysis in HVEM/BTLA-KO mice with Foxp3 reporters; mast cell reconstitution in MC-deficient mice with TNFRSF14-KO MCs; pulldown and EAE model for SALM5

    PMID:27152329 PMID:27793593 PMID:27982078

    Open questions at the time
    • SALM5–HVEM interaction awaits structural validation and independent confirmation
    • Mast cell HVEM signaling intermediates beyond NF-κB not defined
    • Whether CD5 upregulation is a direct HVEM transcriptional target unclear
  14. 2018 High

    HVEM signaling in ILC3 was shown to drive protective IFN-γ production during enteric bacterial infection, extending HVEM's mucosal defense role to innate lymphoid cells.

    Evidence Conditional HVEM KO in ILC3, adoptive transfer of IFN-γ-KO ILC3, Yersinia oral infection model

    PMID:30092201

    Open questions at the time
    • Signaling intermediates linking HVEM to IFN-γ transcription in ILC3 not identified
    • Whether LIGHT is the sole activating ligand for ILC3-HVEM in vivo not confirmed
  15. 2019 High

    Crystal structure of CD160–HVEM confirmed that CD160 shares the CRD1 binding surface with BTLA, and mechanistic studies showed that BTLA on T cells recruits SHP1 to suppress TCR signaling and CD40L mobilization, establishing the molecular basis for HVEM-dependent GC B cell lymphoma suppression.

    Evidence X-ray crystallography of CD160:HVEM; BTLA-KO T cells with SHP1 signaling and CD40L imaging in Bcl-2 transgenic lymphomagenesis model

    PMID:31204070 PMID:31230945

    Open questions at the time
    • Whether CD160 delivers inhibitory or activating signals through HVEM in vivo not fully resolved
    • Relative contributions of SHP1 vs SHP2 to BTLA-mediated suppression of TCR signaling not quantified
  16. 2021 High

    Crystal structures of HVEM with LIGHT and a ternary HVEM–LIGHT–CD160 complex definitively showed that TNF and Ig ligands bind non-overlapping surfaces, enabling simultaneous engagement; ligand-selective HVEM knockin mice proved that LIGHT–HVEM drives intestinal bacterial clearance while BTLA/CD160–HVEM ameliorates liver inflammation.

    Evidence X-ray crystallography including ternary complex, knockin mice with ligand-selective HVEM mutations, infection and inflammation models

    PMID:34709351

    Open questions at the time
    • How simultaneous ternary engagement alters net signaling output quantitatively is unclear
    • Whether the ternary complex forms physiologically in specific tissues not demonstrated
  17. 2022 High

    Epithelial HVEM was shown to sustain intraepithelial T cells by a previously unrecognized mechanism: LIGHT-HVEM signaling induces epithelial collagen IV, which engages β1 integrins on IETs to promote survival and motility.

    Evidence Epithelial HVEM conditional KO, organoid RNA-seq, intravital microscopy, β1 integrin KO T cells, Salmonella infection model

    PMID:35905286

    Open questions at the time
    • Signaling pathway from HVEM to collagen IV transcription in epithelial cells not fully mapped
    • Whether this axis operates outside the gut epithelium unknown
  18. 2024 High

    HVEM on regulatory T cells in the tumor microenvironment was identified as a functional ligand that engages BTLA on CAR T cells, recruiting SHP-1/SHP-2 to suppress CAR signaling; BTLA deletion in CAR T cells enhanced anti-tumor efficacy, validating the HVEM–BTLA axis as a therapeutic target in adoptive cell therapy.

    Evidence CRISPR BTLA-KO in CAR T cells, co-culture with HVEM+ Tregs, phosphatase recruitment assays, in vivo lymphoma and solid tumor models

    PMID:38831106

    Open questions at the time
    • Whether HVEM on other TME cell types contributes to CAR T suppression not addressed
    • Long-term safety of BTLA-deleted CAR T cells not evaluated

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include the signaling intermediates linking HVEM to STAT3 and Akt in different cell types, how the cis-BTLA:HVEM complex is physiologically disrupted during activation, the structural basis for SALM5–HVEM interaction, and whether ternary HVEM–LIGHT–CD160 complexes form in vivo and alter net signaling output.
  • Adaptor proteins linking HVEM to Akt not identified
  • Mechanism of cis-to-trans switch during T cell activation undefined
  • SALM5–HVEM structural and biophysical characterization absent
  • Physiological relevance of ternary complex in specific tissues not demonstrated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 5 GO:0098772 molecular function regulator activity 5
Localization
GO:0005886 plasma membrane 5
Pathway
R-HSA-168256 Immune System 8 R-HSA-162582 Signal Transduction 6 R-HSA-1643685 Disease 4
Partners
BTLACD160LTAPTPN11PTPN6TNFSF14TRAF2TRAF5
Complex memberships
cis-BTLA:HVEM complex

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 HVEM (TNFRSF14) directly binds herpes simplex virus glycoprotein D (gD) via its cysteine-rich pseudorepeats, and this physical interaction mediates HSV entry into HVEM-expressing cells. The gD-HVEM complex has a 1:2 molar ratio (gD:HVEM) and approximately 113 kDa by gel filtration. gD binding is dependent on native gD conformation but independent of N-linked oligosaccharides. Recombinant protein binding assays (ELISA, gel filtration chromatography), competition studies, CHO cell infection assays Journal of virology High 9223502
1997 HVEM 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) results in synergistic NF-κB activation, suggesting distinct roles for each TRAF protein. Yeast two-hybrid, co-immunoprecipitation, NF-κB reporter assay The Journal of biological chemistry High 9153189
2001 X-ray crystal structure of HSV gD alone and in complex with the HVEM ectodomain revealed that gD contains a V-like immunoglobulin fold; the N-terminal hairpin of gD forms the receptor-binding segment and contacts HVEM CRD1, with a conformational change accompanying binding that may be part of the viral entry mechanism. X-ray crystallography Molecular cell High 11511370
2001 The gD-binding domain of HVEM requires both CRD1 and CRD2 (residues 1–120); CRD1 alone or CRD2 alone is insufficient for gD binding. A monoclonal antibody recognizing a discontinuous epitope in CRD1 blocks gD binding, localizing the primary gD contact site to CRD1. Biosensor binding assays, ELISA, virus entry blocking with soluble HVEM truncation mutants and monoclonal antibodies Journal of virology High 11119586
2002 Structure-based mutagenesis of the gD-binding site on HVEM identified Y23 (CRD1) as a critical hot-spot residue that protrudes into a crevice on gD; a C37-C19 disulfide bond in CRD1 is essential for gD binding; CRD2 provides structural support for the CRD1 gD-binding site. HVEM-R75A showed enhanced gD binding. Alanine-scanning mutagenesis, gD binding assays, HSV entry assays Journal of virology High 12368332
2003 Structure-based mutagenesis of gD defined three critical contact regions at the gD-HVEM interface: (i) residues forming an intermolecular β-sheet with HVEM, (ii) residues contacting HVEM-Y23, and (iii) one gD residue contacting HVEM CRD2. None of the gD mutations prevented nectin-1 binding, demonstrating that the gD binding surfaces for HVEM and nectin-1 are distinct. Site-directed mutagenesis, receptor binding assays, virus entry assay, cell-cell fusion assay Journal of virology High 12829851
2005 Crystal structure of the BTLA-HVEM complex at 2.8 Å resolution showed that 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 adopts an Ig I-set fold; BTLA is monomeric in solution and forms a 1:1 complex with HVEM. Alanine-scanning mutagenesis of HVEM further defined critical binding residues. X-ray crystallography, light scattering, alanine-scanning mutagenesis The Journal of biological chemistry High 16169851
2000 gD, LT-α, and LIGHT bind to distinct but overlapping sites on HVEM; peptide ligands differentially inhibit gD versus LT-α binding, and binding of one ligand to HVEM alters the receptor conformation, affecting binding of other ligands. Competitive binding assays with recombinant HVEM truncation mutants and peptide inhibitors, ELISA Molecular immunology Medium 11164894
2009 BTLA and HVEM form a cis heterodimeric complex on the surface of naive T cells that inhibits HVEM-dependent NF-κB RelA activation. The cis-BTLA ectodomain competitively blocks trans-engagement of BTLA and CD160 with HVEM. LIGHT can bind the cis-complex but NF-κB activation is attenuated, suggesting BTLA prevents HVEM oligomerization in cis. HSV gD forms a cis-complex with HVEM but promotes NF-κB activation. Co-immunoprecipitation, NF-κB reporter assays, FACS-based binding assays, genetic deletion experiments, pharmacological disruption Journal of immunology High 19915044
2010 HVEM engagement of BTLA produces inhibitory signals through SHP-1 and SHP-2 association; conversely, BTLA engagement of HVEM produces proinflammatory signals via NF-κB activation, establishing a bidirectional signaling system between the TNFR and Ig superfamilies. Biochemical signaling assays, co-immunoprecipitation (as reviewed with reference to primary experimental findings) Annual review of immunology Medium 20307212
2008 In a T cell transfer colitis model, HVEM expressed by radioresistant innate immune cells (not donor T cells) interacts with BTLA to prevent intestinal inflammation. Loss of HVEM in Rag−/− recipients dramatically accelerated colitis, demonstrating an anti-inflammatory role for HVEM-BTLA signaling in the gut microenvironment. T cell transfer colitis model with HVEM-deficient mice, bone marrow chimeras, in vivo genetic epistasis The Journal of experimental medicine High 18519647
2008 HVEM-BTLA signaling provides an inhibitory checkpoint for dendritic cell homeostasis in lymphoid tissue. HVEM- or BTLA-deficient mice have overpopulated CD8α− DC subsets with a specific growth advantage; both DC-intrinsic and microenvironment expression are required. The LTβR pathway provides positive growth signals that are counter-regulated by HVEM-BTLA. Competitive bone marrow chimeric mice, flow cytometry of DC subsets, LTβR agonist antibody treatment, genetic KO Journal of immunology High 18097025
2011 HVEM promotes the persistence of memory T helper cells (Th1 and Th2) by activating PKB/Akt survival signaling. HVEM-deficient memory CD4 T cells display reduced Akt activity and fail to persist after antigen rechallenge; constitutively active Akt rescues their survival. LIGHT on T cells recapitulates the HVEM effect, suggesting T cell-to-T cell LIGHT-HVEM interactions maintain memory pools. Antigen-specific memory T cell transfer, intracellular signaling assays (Akt phosphorylation), constitutively active Akt rescue, HVEM-KO and LIGHT-KO mice The Journal of experimental medicine High 21402741
2016 Loss of HVEM (TNFRSF14) in germinal center B cells leads to cell-autonomous B cell proliferation and drives GC lymphoma development in vivo. HVEM-deficient B cells also induce a tumor-supportive microenvironment with increased TFH recruitment. Disruption of HVEM-BTLA inhibitory cell-cell interactions underlies these effects. The HVEM ectodomain protein (solHVEM) binds BTLA and restores tumor suppression. In vivo mouse lymphoma model, HVEM-KO B cell adoptive transfer, solHVEM protein administration, CAR-T cell engineering Cell High 27693350
2019 HVEM on B cells restrains T follicular helper cell help to germinal center B cells through the BTLA-SHP1 axis: BTLA on T cells recruits SHP1, reduces TCR signaling, and limits preformed CD40L mobilization to the immunological synapse. T cell 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-deficient T cells, phosphatase (SHP1) signaling assays, imaging of CD40L at the immunological synapse, Bcl-2 transgenic mouse model, in vivo lymphomagenesis model Immunity High 31204070
2016 TNFRSF14 (HVEM) expressed on mast cells is engaged by TNFSF14 (LIGHT), enhancing IgE-mediated mast cell signaling and mediator production. In mouse asthma models, TNFRSF14 blockade or genetic deletion of Tnfrsf14 reduces antigen-specific IgE/IgG1, airway hyperreactivity, inflammation, and remodelling. Engraftment of TNFRSF14-deficient mast cells into mast-cell-deficient mice confirmed that MC-expressed TNFRSF14 is required for multiple asthma features. MC-deficient mice reconstituted with TNFRSF14-KO or WT MCs, anti-TNFRSF14 neutralizing antibody, in vitro IgE-mediated signaling assays, in vivo asthma model Nature communications High 27982078
2016 BTLA expressed on DEC205+CD8+CD11c+ dendritic cells promotes induction of extrathymic Foxp3+ regulatory T cells. HVEM engagement on T cells upregulates CD5, which enables Foxp3 expression by allowing T cells to resist cytokine-driven effector differentiation. In the absence of BTLA/HVEM, T cells remain CD5lo and fail to express Foxp3. DC subset-specific BTLA expression analysis, HVEM-KO and BTLA-KO mice, Foxp3 reporter system, CD5 expression assays, tolerance induction experiments Immunity High 27793593
2019 Crystal structure of CD160 bound to HVEM reveals that CD160 adopts a unique Ig fold variant and forms a 1:1 complex with HVEM using a binding interface similar to that of BTLA:HVEM, overlapping on the CRD1 surface of HVEM. X-ray crystallography, solution stoichiometry analysis Structure High 31230945
2021 Crystal structures of HVEM with LIGHT and with BTLA/CD160 define distinct non-overlapping binding surfaces on HVEM: the TNF ligand LIGHT binds one face while BTLA and CD160 bind CRD1. A ternary HVEM-LIGHT-CD160 complex was determined showing simultaneous engagement. HVEM knockin mutant mice selectively recognizing TNF or Ig ligands demonstrated that LIGHT-HVEM interactions are specifically required for intestinal bacterial clearance, while Ig ligand (BTLA/CD160)-HVEM interactions specifically ameliorate liver inflammation. X-ray crystallography (ternary complex), site-directed mutagenesis, knockin mice with ligand-selective HVEM mutants, in vivo infection model, liver inflammation model The Journal of experimental medicine High 34709351
2022 Epithelial HVEM, stimulated by LIGHT, promotes survival of intraepithelial T cells (IETs) by upregulating epithelial synthesis of collagen IV (a basement membrane protein), which in turn engages β1 integrins on IETs. This HVEM→collagen IV→β1 integrin axis maintains IET number, patrolling movement, and protective responses to Salmonella enterica. HVEM-KO in intestinal epithelium, RNA-seq of organoids treated with HVEM ligands, intravital microscopy, β1 integrin KO T cells, Salmonella infection model Science immunology High 35905286
2024 BTLA on CAR T cells interacts in trans with HVEM expressed on regulatory T cells in the tumor microenvironment, leading to recruitment of tyrosine phosphatases SHP-1 and SHP-2 that inhibit CAR signaling. Deletion of BTLA in CAR T cells improves tumor control and persistence by enhancing CAR signaling and effector function. BTLA-KO in CAR T cells (CRISPR), co-culture with HVEM-expressing Tregs, phosphatase recruitment assays, in vivo lymphoma and solid tumor models Nature immunology High 38831106
2011 HVEM activates a STAT3 signaling pathway in intestinal epithelial cells (in addition to NF-κB), with STAT3 regulating genes important for host defense and influencing differentiation of Th17 cells and innate lymphoid cells. Signaling assays in epithelial cells, HVEM stimulation experiments (as described in primary studies referenced in the review) Gut microbes Medium 23333859
2013 HSV-1 latency-associated transcript (LAT) upregulates HVEM expression in latently infected neurons, and HVEM-deficient mice show significantly reduced HSV-1 latency and reactivation. Two LAT small noncoding RNAs bind the HVEM promoter, proposing a mechanism whereby LAT increases HVEM expression to promote neuronal survival and immune evasion during latency. Hvem−/− mouse latency model, in vitro LAT expression with HVEM promoter assays, LAT noncoding RNA binding studies Journal of virology Medium 24307582
2016 SALM5 (a neuron-specific synaptic adhesion molecule) interacts with HVEM as a functional receptor to suppress CNS inflammation. Anti-SALM5 antibody promoted inflammation in the CNS and aggravated experimental autoimmune encephalomyelitis symptoms, identifying HVEM as a mediator of SALM5-dependent CNS immune privilege. Pulldown/interaction assay, anti-SALM5 monoclonal antibody treatment, EAE mouse model, LPS-induced CNS inflammation Science advances Medium 27152329
2018 HVEM signaling in ILC3 innate lymphoid cells, stimulated by LIGHT, drives protective IFN-γ secretion during Yersinia enterocolitica oral infection. Mice with HVEM-deficient ILC3 show reduced IFN-γ, higher bacterial burdens, and increased mortality; adoptive transfer of WT but not IFN-γ-deficient ILC3 restores protection. Conditional HVEM KO in ILC3, adoptive transfer of IFN-γ-KO ILC3, Yersinia oral infection model Cell host & microbe High 30092201
2008 HSV-1 gD interaction with HVEM (but not a HVEM-binding-incompetent gD mutant) activates NF-κB-dependent anti-apoptotic signaling in HVEM-expressing cells. Blocking gD-HVEM interaction with specific MAbs or using an HVEM-non-binding gD mutant abolishes protection against Fas-mediated apoptosis, demonstrating that NF-κB survival signaling requires gD-HVEM engagement. MAb blocking of gD-HVEM interaction, gD point mutants unable to bind HVEM, apoptosis assays in HVEM-expressing cells vs. control cells Biochemical pharmacology High 18723002
2022 In T cell reporter systems, co-expression of LIGHT or CD160 (but not BTLA) with HVEM induces strong constitutive HVEM signaling. In the cis-BTLA:HVEM complex, BTLA-mediated inhibitory signaling is dominant and not impaired, while HVEM co-stimulation by trans-ligands is blocked. HVEM antibodies can simultaneously act as checkpoint inhibitors and co-stimulation agonists. T cell reporter systems, primary human T cell stimulation assays, co-expression experiments with HVEM and its ligands Frontiers in immunology Medium 36081508

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 254 9223502
2009 The CD160, BTLA, LIGHT/HVEM pathway: a bidirectional switch regulating T-cell activation. Immunological reviews 247 19426226
2016 Loss of the HVEM Tumor Suppressor in Lymphoma and Restoration by Modified CAR-T Cells. Cell 207 27693350
1994 HVEM tomography of the trans-Golgi network: structural insights and identification of a lace-like vesicle coat. The Journal of cell biology 203 7929568
2011 The signaling networks of the herpesvirus entry mediator (TNFRSF14) in immune regulation. Immunological reviews 197 22017438
2005 Preligand assembly domain-mediated ligand-independent association between TRAIL receptor 4 (TR4) and TR2 regulates TRAIL-induced apoptosis. Proceedings of the National Academy of Sciences of the United States of America 189 16319225
2010 Slow down and survive: Enigmatic immunoregulation by BTLA and HVEM. Annual review of immunology 187 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 T cell intrinsic heterodimeric complexes between HVEM and BTLA determine receptivity to the surrounding microenvironment. Journal of immunology (Baltimore, Md. : 1950) 131 19915044
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
1998 Cloning and characterization of mouse RIP140, a corepressor for nuclear orphan receptor TR2. Molecular and cellular biology 113 9774688
2003 LIGHT-HVEM signaling and the regulation of T cell-mediated immunity. Cytokine & growth factor reviews 108 12787566
2011 Nuclear receptors TR2 and TR4 recruit multiple epigenetic transcriptional corepressors that associate specifically with the embryonic β-type globin promoters in differentiated adult erythroid cells. Molecular and cellular biology 106 21670149
2016 Genome-wide analysis of pediatric-type follicular lymphoma reveals low genetic complexity and recurrent alterations of TNFRSF14 gene. Blood 104 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
2002 An embryonic/fetal beta-type globin gene repressor contains a nuclear receptor TR2/TR4 heterodimer. The EMBO journal 98 12093744
1989 Molecular cloning of new human TR2 receptors: a class of steroid receptor with multiple ligand-binding domains. Biochemical and biophysical research communications 94 2597158
2010 Regulation of inflammation, autoimmunity, and infection immunity by HVEM-BTLA signaling. Journal of leukocyte biology 92 21106644
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
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
2003 Induction of caspase 8 by interferon gamma renders some neuroblastoma (NB) cells sensitive to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) but reveals that a lack of membrane TR1/TR2 also contributes to TRAIL resistance in NB. Cancer research 87 12615731
2002 Recent advances in the TR2 and TR4 orphan receptors of the nuclear receptor superfamily. The Journal of steroid biochemistry and molecular biology 79 12361719
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
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
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
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
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
1995 Multiple functions of the TR2-11 orphan receptor in modulating activation of two key cis-acting elements involved in the retinoic acid signal transduction system. The Journal of biological chemistry 57 8530418
2005 The evolving crosstalk between co-stimulatory and co-inhibitory receptors: HVEM-BTLA. Trends in immunology 56 15922943
2021 Isolation and Characterization of a Novel Salmonella Phage vB_SalP_TR2. Frontiers in microbiology 55 34234757
2021 BTLA-HVEM Couple in Health and Diseases: Insights for Immunotherapy in Lung Cancer. Frontiers in oncology 55 34532285
1995 Identification of human TR2 orphan receptor response element in the transcriptional initiation site of the simian virus 40 major late promoter. The Journal of biological chemistry 54 7890658
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 53 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
2007 The TR2 and TR4 orphan nuclear receptors repress Gata1 transcription. Genes & development 45 17974920
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 43 8241550
2019 Mechanism of regulation and neutralization of the AtaR-AtaT toxin-antitoxin system. Nature chemical biology 41 30718814
1989 Three-dimensional morphometrical study of dendritic spines of the granule cell in the rat dentate gyrus with HVEM stereo images. Journal of electron microscopy technique 41 2760687
2021 BTLA/HVEM Axis Induces NK Cell Immunosuppression and Poor Outcome in Chronic Lymphocytic Leukemia. Cancers 40 33917094
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
2016 Neuron-specific SALM5 limits inflammation in the CNS via its interaction with HVEM. Science advances 40 27152329
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 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
2017 Expression and Clinical Significance of Herpes Virus Entry Mediator (HVEM) in Breast Cancer. Annals of surgical oncology 37 28612127
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
2000 The three HveA receptor ligands, gD, LT-alpha and LIGHT bind to distinct sites on HveA. Molecular immunology 36 11164894
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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 33 27982078
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 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
2015 Cutting Edge: the BTLA-HVEM regulatory pathway interferes with protective immunity to intestinal Helminth infection. Journal of immunology (Baltimore, Md. : 1950) 31 25595777
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
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1998 A bidirectional regulation between the TR2/TR4 orphan receptors (TR2/TR4) and the ciliary neurotrophic factor (CNTF) signaling pathway. The Journal of biological chemistry 29 9694834
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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
2021 Blockade of HVEM for Prostate Cancer Immunotherapy in Humanized Mice. Cancers 27 34208480
2007 Blockade of LIGHT/HVEM and B7/CD28 signaling facilitates long-term islet graft survival with development of allospecific tolerance. Transplantation 27 17893608
2001 The orphan nuclear receptor TR2 interacts directly with both class I and class II histone deacetylases. Molecular endocrinology (Baltimore, Md.) 27 11463856
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
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2009 Role of nectin-1, HVEM, and PILR-alpha in HSV-2 entry into human retinal pigment epithelial cells. Investigative ophthalmology & visual science 26 19234349
2021 Frequent mutated B2M, EZH2, IRF8, and TNFRSF14 in primary bone diffuse large B-cell lymphoma reflect a GCB phenotype. Blood advances 25 34478526
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2007 Orphan nuclear receptor TR2, a mediator of preadipocyte proliferation, is differentially regulated by RA through exchange of coactivator PCAF with corepressor RIP140 on a platform molecule GRIP1. Nucleic acids research 25 17389641
2005 Lymphtoxin beta receptor-Ig ameliorates TNBS-induced colitis via blocking LIGHT/HVEM signaling. Pharmacological research 25 15925518
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2016 Knockdown of HVEM, a Lymphocyte Regulator Gene, in Ovarian Cancer Cells Increases Sensitivity to Activated T Cells. Oncology research 24 27458100
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