Affinage

TNFSF9

Tumor necrosis factor ligand superfamily member 9 · UniProt P41273

Length
254 aa
Mass
26.6 kDa
Annotated
2026-06-10
100 papers in source corpus 31 papers cited in narrative 30 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TNFSF9 (4-1BBL/CD137L) is a trimeric TNF-superfamily ligand that serves as a bidirectional immune co-stimulator, transmitting forward signals through its receptor 4-1BB (CD137) and receptor-independent reverse signals into the cells that express it (PMID:30410017, PMID:17496895). Structurally, human 4-1BBL assembles as a canonical bell-shaped trimer and engages 4-1BB predominantly at one protomer via the inter-protomer crevice using a non-canonical mechanism lacking the typical DE-loop tyrosine contact; human 4-1BB additionally forms CRD4 disulfide-linked dimers that crosslink complexes into a 2D network to amplify signaling (PMID:30410017, PMID:29720398, PMID:29720399). Mouse 4-1BBL diverges as a covalent disulfide-linked dimer that binds via the GH loop, a species difference proposed to be compensated by galectin-9-mediated receptor aggregation (PMID:30545939, PMID:29242193). Soluble trimeric 4-1BBL alone is insufficient for co-stimulation; crosslinking of two trimers or targeted surface presentation is the minimal requirement for co-stimulatory activity (PMID:16204238, PMID:18779748). Through forward signaling, 4-1BBL augments suboptimal CTL responses (PMID:10528184), drives TRAF1-dependent downregulation of pro-apoptotic Bim to promote CD8 T cell expansion (PMID:18056369), suppresses TGF-β-driven Treg conversion via IFN-γ (PMID:22870329), and restrains myelopoiesis and dendritic cell differentiation (PMID:18604213). In its reverse-signaling capacity, surface 4-1BBL on macrophages forms a complex with TLR4 that recruits TIRAP, IRAK2 and the TRAF6/TAK1/TAB1 module to sustain late-phase CREB/C-EBP-dependent TNF production independent of 4-1BB, MyD88 and TRIF (PMID:17496895, PMID:24084649), and reprograms macrophage glucose metabolism through AKT-mTOR to support proliferation and inflammation (PMID:32041783, PMID:25691217). Reverse signaling also induces CXCL1/CXCL2-driven neutrophil recruitment in epithelial cells during ischemia-reperfusion injury (PMID:22160719) and NF-κB-dependent monocyte differentiation into inflammatory dendritic cells (PMID:19684160). A homozygous TNFSF9 missense mutation (p.V140G) abolishing surface CD137L causes loss of 4-1BB-mediated co-stimulation and failure of EBV-specific T cell expansion, with rescue upon restoring CD137L (PMID:35657354).

Mechanistic history

Synthesis pass · year-by-year structured walk · 25 steps
  1. 1997 Medium

    Established that 4-1BBL/4-1BB binding involves species-specific properties, with murine 4-1BB binding ECM laminin in a manner mutually exclusive with ligand, a feature not conserved in human.

    Evidence Binding competition and domain-mapping with truncated fragments and murine/human chimeras

    PMID:9045669

    Open questions at the time
    • No structural basis for the species difference resolved at this stage
    • Functional consequence of laminin binding in vivo not established
  2. 1999 High

    Defined 4-1BBL as a co-stimulator that augments suboptimal CTL responses, separable from CD28, by showing genetic deficiency impairs antiviral and allograft responses.

    Evidence 4-1BBL-/- and 4-1BBL-/-CD28-/- mice across influenza, LCMV, and allograft models with soluble receptor blocking

    PMID:10528184

    Open questions at the time
    • Downstream signaling intermediates not identified
    • Antigen-strength dependence mechanism unexplained
  3. 2005 High

    Resolved the oligomeric requirement for co-stimulation, showing soluble trimeric ligand is insufficient and crosslinking of two trimers is the minimal activating step.

    Evidence Recombinant 4-1BBL, ultracentrifugation/gel filtration, SPR, C51 mutagenesis, and T cell proliferation assays

    PMID:16204238

    Open questions at the time
    • Physiological crosslinking mechanism on cell surfaces not defined
    • Role of Cys-51 disulfide in vivo unclear
  4. 2007 High

    Identified a receptor-independent reverse-signaling function: surface 4-1BBL on macrophages associates with TLR4 to sustain late-phase TNF production via CREB/C-EBP, independent of MyD88/TRIF.

    Evidence Reciprocal Co-IP, 4-1BBL-deficient macrophages, and NF-κB/CREB/C-EBP reporter and cytokine assays

    PMID:17496895

    Open questions at the time
    • Adaptors bridging TLR4-4-1BBL not yet identified
    • How early signaling triggers ligand translocation unknown
  5. 2007 Medium

    Defined a forward signaling effector: 4-1BBL co-stimulation downregulates pro-apoptotic Bim via TRAF1 to promote CD8 T cell survival.

    Evidence TRAF1 siRNA knockdown with intracellular Bim measurement and antigen-specific CD8 expansion assays

    PMID:18056369

    Open questions at the time
    • Single-lab siRNA loss-of-function
    • Link between TRAF1 and Bim regulation mechanistically incomplete
  6. 2008 High

    Showed 4-1BBL forward signaling restrains myelopoiesis and DC differentiation at the progenitor level.

    Evidence 4-1BB-/- and 4-1BBL-/- mice, bone marrow chimeras, and in vitro differentiation assays

    PMID:18604213

    Open questions at the time
    • Intracellular signaling controlling progenitor inhibition not defined
  7. 2009 Medium

    Extended reverse signaling to monocytes, showing 4-1BBL engagement drives NF-κB-dependent differentiation into Th1-inducing dendritic cells.

    Evidence Anti-4-1BBL mAb stimulation, NF-κB nuclear translocation, and cytokine neutralization (GM-CSF/M-CSF/Flt3L)

    PMID:19684160

    Open questions at the time
    • Antibody-driven rather than physiological ligand engagement
    • Proximal signaling components linking ligand to NF-κB unidentified
  8. 2011 High

    Demonstrated reverse signaling drives tissue pathology: CD137 on NK cells engages epithelial CD137L to induce CXCL1/CXCL2 and neutrophil recruitment in kidney ischemia-reperfusion injury.

    Evidence CD137-/- and CD137L-/- mice in an IRI model with chemokine measurement and neutrophil depletion

    PMID:22160719

    Open questions at the time
    • Intracellular reverse-signaling cascade in epithelial cells not mapped
  9. 2013 High

    Identified the molecular intermediates of macrophage reverse signaling, placing TIRAP and IRAK2 between the TLR4-4-1BBL complex and TRAF6/TAK1-driven sustained TNF.

    Evidence Co-IP, TIRAP-/- and IRAK2-/- mice, dominant-negative constructs, and an LPS sepsis model

    PMID:24084649

    Open questions at the time
    • Structural basis of the TLR4-4-1BBL interaction unknown
    • How 4-1BBL recruits TIRAP/IRAK2 mechanistically unclear
  10. 2012 Medium

    Showed 4-1BBL forward co-stimulation blocks induced Treg conversion through IFN-γ.

    Evidence SA-4-1BBL oligomer, IFN-γ neutralization, in vitro iTreg conversion, and an in vivo tumor model

    PMID:22870329

    Open questions at the time
    • Single-lab; uses engineered oligomeric ligand
    • Direct vs indirect IFN-γ contribution not fully separated
  11. 2012 Medium

    Extended bidirectional signaling to metabolic inflammation, with 4-1BB/4-1BBL contact between adipocytes and macrophages activating MAPK/Akt/IκBα and inflammatory cytokine release.

    Evidence Adipocyte-macrophage co-culture, agonists, signaling analysis, and blocking antibodies

    PMID:23316108

    Open questions at the time
    • Forward vs reverse signaling contributions not disentangled
    • Single-lab co-culture system
  12. 2015 Medium

    Defined the metabolic basis of reverse signaling, showing 4-1BBL reprograms glucose metabolism via AKT-mTOR to drive macrophage proliferation.

    Evidence 4-1BBL stimulation, glucose uptake assays, GLUT1/glycolytic enzyme analysis, and 2-DG inhibition

    PMID:25691217

    Open questions at the time
    • Receptor-independence not formally controlled in this study
    • Single-lab metabolic readouts
  13. 2015 Medium

    Identified a soluble decoy mechanism, where hypoxia-induced soluble CD137 binds CD137L on APCs and blocks T cell co-stimulation, promoting tumor immune escape.

    Evidence Hypoxia, splice-variant RT-PCR, ELISA, T cell co-culture blocking, shRNA, and in vivo tumor immunogenicity

    PMID:26942078

    Open questions at the time
    • Single-lab; physiological abundance of sCD137 in human tumors not quantified
  14. 2015 Medium

    Connected TNFSF9 expression to epigenetic/post-transcriptional control, with miR-484 loss via CpG methylation derepressing CD137L to promote IL-8 in MSI colorectal cancer.

    Evidence miRNA microarray, methylation analysis, miR-484 gain/loss, and IL-8 measurement

    PMID:25727216

    Open questions at the time
    • Direct miR-484-TNFSF9 binding interaction confirmation limited to single lab
  15. 2017 Medium

    Showed CD137-CD137L signaling drives vascular smooth muscle phenotype switching through NFATc1 activation.

    Evidence Recombinant CD137L, NFATc1 siRNA/overexpression, migration assays, and an in vivo neointima model

    PMID:28770466

    Open questions at the time
    • Forward vs reverse signaling directionality not resolved
    • Single-lab
  16. 2017 High

    Provided structural detail of the murine receptor, revealing distinct CRD organization and CRD4 N-glycans that mediate galectin-9 binding, supporting a model where galectin-9 aids aggregation of the dimeric mouse system.

    Evidence X-ray crystallography of m4-1BB, SPR kinetics, and glycosylation mapping

    PMID:29242193

    Open questions at the time
    • Functional role of galectin-9 aggregation in signaling not directly tested in vivo
  17. 2018 High

    Resolved the long-disputed ligand architecture, establishing the human 4-1BBL bell-shaped trimer and a non-canonical inter-protomer binding mode, and defining how receptor CRD4 disulfide dimers amplify signaling.

    Evidence Multiple independent crystal structures of complex, free ligand, and antibody-bound receptor, with mutagenesis and cell-based agonist assays

    PMID:29720398 PMID:29720399 PMID:30410017

    Open questions at the time
    • Dynamics of 2D network formation on living cell surfaces not directly visualized
  18. 2018 High

    Clarified the species divergence in ligand assembly, defining mouse 4-1BBL as a covalent dimer with GH-loop-mediated receptor selectivity.

    Evidence Crystal structures of free and complexed m4-1BBL with structure-guided interface mutagenesis

    PMID:30545939

    Open questions at the time
    • How the dimeric mouse geometry achieves productive clustering not fully resolved without galectin contribution
  19. 2022 High

    Provided definitive human causal genetics, showing a homozygous TNFSF9 loss-of-function mutation abolishes CD137L surface expression and EBV-specific T cell expansion, rescued by CD137L restoration.

    Evidence Patient genetics, ectopic wild-type vs mutant expression, and rescue of EBV-specific T cell expansion

    PMID:35657354

    Open questions at the time
    • Full clinical spectrum of TNFSF9 deficiency beyond EBV immunity not delineated
  20. 2022 Medium

    Identified galectin-3 as a modulator that suppresses 4-1BBL bioactivity by clustering receptor into large complexes rather than competing for binding.

    Evidence Co-binding assays, plasma particle sizing, flow cytometry, and TNFα production on 4-1BB-transfected cells

    PMID:35812455

    Open questions at the time
    • In vivo relevance of galectin-3 modulation not established
    • Single-lab
  21. 2022 Medium

    Showed leukemic extracellular vesicles can deliver surface 4-1BBL to promote suppressive effector Tregs, expanding the modes of ligand presentation.

    Evidence Leukemic EV isolation, Rab27a-deficient mice, Treg functional assays, and transcriptomics

    PMID:35130345

    Open questions at the time
    • Whether vesicular 4-1BBL signals forward, reverse, or both not separated
    • Single-lab
  22. 2022 Medium

    Extended reverse-signaling-like activity to lymphangiogenesis, with macrophage-derived CD137L activating CD137 on lymphatic endothelial cells to drive PI3K/AKT/mTOR-dependent autophagy.

    Evidence Recombinant CD137L, CD137 and Atg5/Atg7 siRNA, pathway analysis, functional LEC assays, and a UUO model

    PMID:35173546

    Open questions at the time
    • Single-lab; receptor-side signaling rather than ligand reverse signaling
  23. 2023 Medium

    Placed 4-1BBL within an innate-to-NK co-stimulatory axis, where macrophage STING-NLRP3 signaling induces 4-1BBL to enhance NK antitumor function.

    Evidence STING-/- and NLRP3-/- mice, NK depletion, macrophage/NK co-culture, and a CRC liver metastasis model

    PMID:36927529

    Open questions at the time
    • Single-lab; direct contribution of 4-1BBL versus IL-18/IL-1β partly inferred
  24. 2024 Medium

    Defined 4-1BBL on Batf3-lineage dendritic cells as a major co-stimulatory signal required for CD8 T cell reinvigoration during PD-1/PD-L1 blockade.

    Evidence Batf3-/- mice, anti-4-1BBL blocking, flow cytometry, and spatial transcriptomics on human tumors

    PMID:38656869

    Open questions at the time
    • Single-lab; molecular determinants of DC-restricted ligand activity not detailed
  25. 2024 Medium

    Linked tumor metabolism to TNFSF9 transcription, showing glioma-derived lactate drives macrophage H3K18 lactylation that upregulates TNFSF9 and promotes M2 polarization.

    Evidence ChIP-seq for H3K18La, MCT-1 and TNFSF9 knockdown, glycolysis inhibition, and in vivo glioma models

    PMID:39010835

    Open questions at the time
    • Single-lab; whether the M2 effect requires 4-1BBL signaling versus correlated expression not fully separated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the same trimeric ligand selects between forward co-stimulation and distinct reverse-signaling cascades in different cell types, and the structural/adaptor basis for assembling the reverse-signaling TLR4-4-1BBL-TIRAP-IRAK2 platform, remain unresolved.
  • No structure of the 4-1BBL reverse-signaling complex with TLR4/TIRAP/IRAK2
  • Cytoplasmic determinants of 4-1BBL reverse signaling not mapped
  • Mechanism partitioning forward versus reverse signaling per cell type unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 4 GO:0060089 molecular transducer activity 4 GO:0005198 structural molecule activity 3
Localization
GO:0005886 plasma membrane 3 GO:0005576 extracellular region 2
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 4 R-HSA-1430728 Metabolism 3
Partners
IRAK2LGALS3LGALS9TIRAPTLR4TNFRSF9TRAF1

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2018 Crystal structures of the human 4-1BB/4-1BBL complex, unbound 4-1BBL, and 4-1BB bound to utomilumab or urelumab were solved, revealing: (1) 4-1BBL forms a canonical bell-shaped trimer (not the previously reported three-bladed propeller), (2) 4-1BB binds predominantly to one protomer of the 4-1BBL trimer at the inter-protomer crevice via a distinct mechanism lacking the canonical DE-loop tyrosine interaction, (3) utomilumab binds 4-1BB CRDs 3–4 and blocks ligand, whereas urelumab binds CRD-1 away from the ligand-binding site, and (4) cell-based assays show utomilumab is a milder agonist than urelumab. X-ray crystallography (structures of complex, ligand alone, and antibody-bound receptor); cell-based functional assays Nature communications High 30410017
2018 Crystal structure of the human 4-1BB/4-1BBL complex at 2.4 Å resolution shows 4-1BBL adopts a canonical bell-shaped trimer (contradicting a previously published propeller structure). Mutational data support this structure as biologically relevant. 4-1BB forms a disulfide-linked dimer via a CRD4 cysteine, and this covalent receptor dimerization can cross-link ligand-receptor complexes into a 2D signaling network, amplifying 4-1BB signaling. X-ray crystallography; site-directed mutagenesis; structural comparison The Journal of biological chemistry High 29720398 29720399
2018 Crystal structure of mouse 4-1BBL reveals a disulfide-linked dimeric assembly (unlike trimeric human 4-1BBL), mediated by Cys-246 and Ser-256 unique to m4-1BBL. Upon m4-1BB binding, m4-1BBL undergoes structural changes within each protomer and inter-subunit rotation. Each receptor monomer binds a single ligand subunit via CRD1, CRD2, and CRD3, with the GH loop (not DE loop) providing energetically critical contacts defining receptor selectivity. X-ray crystallography; structure-guided mutagenesis of binding interface The Journal of biological chemistry High 30545939
2017 Crystal structure of murine 4-1BB at 2.2 Å resolution reveals four cysteine-rich domains (CRDs) with CRD1 organization and CRD3/4 orientation distinct from other TNFRSFs. Two Asn residues within CRD4 are N-linked glycosylated and mediate m4-1BB binding to galectin-9 (Gal-9). Both N- and C-terminal domains of Gal-9 bind m4-1BB (with lower affinity than m4-1BBL). m4-1BBL forms a covalent dimer (via two cysteines absent in h4-1BBL), and since m4-1BBL can recruit only two m4-1BB monomers, Gal-9 is proposed to aid aggregation for efficient signaling. X-ray crystallography (sulfur-SAD phasing); surface plasmon resonance kinetics; glycosylation mapping The Journal of biological chemistry High 29242193
2005 Recombinant human 4-1BBL (AviTag-4-1BBL) exists as a homotrimer with nanomolar affinity for 4-1BB (Kd ~1.2 nM vs. 55.2 nM for FLAG-4-1BBL). The single extracellular cysteine (Cys-51) can form a disulfide bond in both recombinant and physiologically expressed 4-1BBL. Mutation of Cys-51 does not affect trimerization but increases the dissociation rate from 4-1BB. Soluble trimeric 4-1BBL inhibits PBMC proliferation but does not costimulate purified T cells; crosslinking of two trimeric 4-1BBL molecules is the minimum step required to elicit costimulatory activity. Recombinant protein production; analytical ultracentrifugation/gel filtration for trimerization; surface plasmon resonance; T cell proliferation assays; site-directed mutagenesis (C51 mutant) The Journal of biological chemistry High 16204238
2007 4-1BBL on macrophage surfaces interacts with TLRs to sustain TNF production during late-phase (2–8 h post-LPS) TLR4 signaling. This 4-1BBL function is independent of its receptor 4-1BB and does not require MyD88 or TRIF adaptors. 4-1BBL does not affect early NF-κB activation but is required for late-phase activation of CREB and C/EBP transcription factors. Co-immunoprecipitation showed TLR4-MyD88 complexes form during the first hour, while TLR4-4-1BBL interactions form between 2 and 8 h after LPS. Co-immunoprecipitation; 4-1BBL-deficient macrophages (genetic ablation); reporter assays for NF-κB, CREB, C/EBP; cytokine ELISA Nature immunology High 17496895
2013 4-1BBL mediates late-phase TLR4 signaling by interacting with TIRAP and IRAK2. After TLR4 early signaling induces 4-1bbl expression, 4-1BBL translocates to the plasma membrane and forms a complex with TLR4. This TLR4-4-1BBL complex signals through TIRAP and IRAK2, which recruit the TRAF6/TAK1/TAB1 complex to sustain TNF-α production. Inhibition of this late-phase pathway reduced LPS-induced TNF-α production and ameliorated LPS-induced sepsis in mice. Co-immunoprecipitation; genetic knockouts (TIRAP-/-, IRAK2-/- mice); dominant-negative constructs; LPS-induced sepsis model; cytokine measurement Science signaling High 24084649
2011 Reverse signaling through CD137L (4-1BBL) in tubular epithelial cells (TECs) is required for acute kidney ischemia-reperfusion injury (IRI). CD137 on NK cells engages CD137L on TECs, triggering CD137L reverse signaling that induces TEC production of CXCL1 and CXCL2, driving neutrophil recruitment and a proinflammatory cascade. Genetic experiments showed both CD137 on NK cells and CD137L on TECs are required for this process. Mouse IRI model; genetic knockouts (CD137-/-, CD137L-/- mice); cell-specific expression analysis; cytokine/chemokine measurement; neutrophil depletion Proceedings of the National Academy of Sciences of the United States of America High 22160719
2008 4-1BB and 4-1BBL interactions suppress myelopoiesis: 4-1BBL is expressed on hematopoietic stem cells, common myeloid progenitors (CMPs), and granulocyte-macrophage progenitors (GMPs); 4-1BB is inducible on activated myeloid progenitors. Mice deficient in 4-1BB or 4-1BBL have increased steady-state numbers of GMPs, myeloid-lineage cells, and mature dendritic cells. Bone marrow chimeras and in vitro differentiation assays confirmed that the 4-1BBL on progenitors binds 4-1BB to inhibit myeloid and DC lineage differentiation. 4-1BB-/- and 4-1BBL-/- mice; bone marrow chimeras; flow cytometry; in vitro differentiation assays Nature immunology High 18604213
2007 4-1BBL costimulation leads to TNFR-associated factor 1 (TRAF1)-dependent down-modulation of the pro-apoptotic molecule Bim in activated CD8 T cells. Reducing TRAF1 levels using siRNA resulted in increased Bim levels in 4-1BBL-stimulated T cells, demonstrating TRAF1 is required downstream of 4-1BBL signaling to suppress Bim and thereby increase T cell expansion. siRNA knockdown of TRAF1; intracellular Bim protein measurement; antigen-specific CD8 T cell expansion assays; flow cytometry Journal of immunology (Baltimore, Md. : 1950) Medium 18056369
2009 Reverse signaling of 4-1BBL into monocytes (triggered by anti-4-1BBL antibody) induces their differentiation into potent dendritic cells. This process involves nuclear translocation of NF-κB and requires autocrine signaling from GM-CSF, M-CSF, and Flt3 ligand, as neutralization of these factors inhibited proliferation. The resulting DCs exhibit a Th1-inducing phenotype with elevated IL-12 and IFN-γ and reduced IL-10. Anti-4-1BBL mAb stimulation; NF-κB nuclear translocation assay; neutralizing antibodies against GM-CSF, M-CSF, and Flt3L; cytokine ELISA; flow cytometry International immunology Medium 19684160
2020 4-1BBL signaling in macrophages is dependent on glycolysis for early TLR-induced 4-1BBL expression, and the sustained late-phase 4-1BBL-mediated inflammatory response depends on glycolysis and fatty acid synthesis. Genetic ablation or antibody blockade of 4-1BBL signaling alleviated imiquimod-induced psoriasis and regulated macrophage polarization in vitro. The psoriasis-promoting effect of 4-1BBL was independent of its receptor 4-1BB (4-1BB deficiency augmented psoriasis severity through different mechanisms). 4-1BBL-/- and 4-1BB-/- mice; metabolic inhibitors (2-DG, cerulenin); anti-4-1BBL antibody; 4-1BB-Fc decoy; imiquimod psoriasis model; cytokine measurement Journal of immunology (Baltimore, Md. : 1950) Medium 32041783
2015 4-1BBL signaling promotes macrophage/monocyte proliferation by reprogramming glucose metabolism via AKT-mTOR signaling. 4-1BBL stimulation increased glucose uptake, GLUT1 expression, glycolytic enzyme levels, lactate production, and transcription of pentose phosphate pathway and lipogenesis genes. 2-deoxyglucose (glycolytic inhibitor) completely abolished 4-1BBL-induced macrophage proliferation. 4-1BBL stimulation on macrophages; glucose uptake assay; Western blot; qRT-PCR; metabolic inhibitor (2-DG); AKT-mTOR pathway analysis The FEBS journal Medium 25691217
2012 4-1BB/4-1BBL interaction promotes bidirectional inflammatory signaling in adipocytes and macrophages. 4-1BB is expressed on adipocytes and upregulated by obesity-related factors, which also enhance 4-1BBL expression on macrophages. 4-1BB and/or 4-1BBL agonists activated MAPK/IκBα and MAPK/Akt signaling in adipocytes and macrophages respectively, and enhanced inflammatory cytokine release (MCP-1, TNF-α, IL-6). Disruption of 4-1BB/4-1BBL interaction in contact co-culture decreased inflammatory cytokine release. Co-culture of adipocytes and macrophages; 4-1BB/4-1BBL agonists; signaling pathway (MAPK, Akt, IκBα) analysis; cytokine ELISA; blocking antibodies Mediators of inflammation Medium 23316108
1999 4-1BBL-/- mice exhibit a weaker CTL response to influenza virus compared to wild-type, while the CTL response to LCMV is normal. 4-1BBL-/-CD28-/- mice show a delay in skin allograft rejection and respond poorly to influenza. CD28-/- T cells show substantially inhibited allogeneic CTL responses to 4-1BBL-expressing APC (blocked by soluble 4-1BB receptor). TCR-transgenic CD28-/- T cells are responsive to 4-1BBL co-stimulation when a suboptimal agonist peptide is used but not with the wild-type peptide, placing 4-1BBL as a co-stimulator that augments suboptimal CTL responses. 4-1BBL-/- and 4-1BBL-/-CD28-/- mice; viral infection models (influenza, LCMV); skin allograft rejection; soluble 4-1BB receptor blocking; CTL assays; TCR-transgenic CD28-/- T cells Journal of immunology (Baltimore, Md. : 1950) High 10528184
2022 Leukemic extracellular vesicles (EVs) shuttle 4-1BBL/CD137L on their surface to promote suppressive effector regulatory T cells (Tregs). 4-1BBL on leukemic EVs promoted suppressive activity and effector phenotype of Tregs by regulating expression of CD30 and TNFR2. Leukemic EV secretion is Rab27a-dependent. Leukemic EV isolation; flow cytometry; Rab27a-deficient mouse model; Treg functional assays; transcriptomic profiling Blood advances Medium 35130345
2022 A homozygous missense mutation (p.V140G) in TNFSF9 (CD137L/4-1BBL) causes a loss-of-function with absent surface expression of CD137L on patient monocytes, dendritic cells, and EBV-infected B cells. Patient EBV-infected B cells failed to trigger expansion of EBV-specific T cells. T cell expansion was recovered when CD137L expression was restored on patient B cells, demonstrating that CD137L is required for CD137-mediated co-stimulation supporting EBV-specific T cell responses. Patient genetics (homozygous TNFSF9 missense mutation); ectopic expression of wild-type vs. mutant CD137L in HEK and P815 cells; flow cytometry; EBV-specific T cell expansion assays; rescue by CD137L restoration The Journal of experimental medicine High 35657354
1997 m4-1BBL binding to m4-1BB blocks laminin (LN) binding, whereas m4-1BB binding to LN does not block m4-1BBL binding. Truncation studies showed regions downstream of the LN-homologous domain participate in LN binding, and the intact protein is required for m4-1BBL binding. Human 4-1BB does not bind ECM proteins, only h4-1BBL, indicating this ECM-binding property is not conserved across species. Binding competition assays; truncated protein fragments; anti-4-1BB monoclonal antibody blocking panel; murine/human chimeras The Journal of biological chemistry Medium 9045669
2008 The scFv36-4-1BBL fusion protein (scFv against FAP fused to 4-1BBL extracellular domain) forms a homotrimeric molecule that binds FAP and 4-1BB simultaneously. T cell costimulation (measured by IFN-γ release) was concentration-dependent, ligand-specific, and substantially constrained to FAP-expressing target cells, demonstrating that targeted presentation of 4-1BBL is required for its co-stimulatory activity. Recombinant fusion protein generation; binding assays to FAP and 4-1BB; co-culture T cell costimulation assay; IFN-γ ELISA Journal of immunotherapy (Hagerstown, Md. : 1997) Medium 18779748
2015 Tumor cell-derived soluble CD137 (sCD137), produced under hypoxic conditions via alternative splicing lacking the transmembrane domain, binds CD137L (4-1BBL) on APCs and prevents interaction of CD137L with transmembrane CD137 on T cells, thereby blocking T cell co-stimulation. shRNA silencing of CD137 in tumor cells rendered tumors more immunogenic in immunocompetent mice but not in immunodeficient or CD8+ T cell-depleted mice. Hypoxia exposure of tumor cell lines; RT-PCR for splice variants; ELISA for sCD137; T cell co-culture with CD137L transfectants; shRNA knockdown; in vivo tumor immunogenicity assays Oncoimmunology Medium 26942078
2003 Anti-4-1BBL monoclonal antibody (1F1) triggers reverse signaling through 4-1BBL on monocytes, inducing monocyte proliferation from peripheral blood. The same antibody inhibited T lymphocyte proliferation costimulated by soluble 4-1BBL and anti-CD3. Anti-4-1BBL mAb generation; flow cytometry; Western blotting; T cell proliferation inhibition assay; monocyte proliferation assay Hybridoma and hybridomics Low 14678652
2008 CD137L-mediated reverse signaling inhibits RANKL-induced osteoclast formation in a dose-dependent manner. Cross-linking of CD137L with anti-CD137L mAb inhibited M-CSF/RANKL-evoked formation of multi-nucleated osteoclasts from bone marrow cells. Anti-CD137L mAb crosslinking; osteoclastogenesis assay from murine bone marrow and RAW264.7 cells; RANKL/M-CSF stimulation Immunobiology Low 19167994
2015 miR-484 directly represses CD137L (TNFSF9) expression in MSI colorectal cancer cells. Loss of miR-484 via CpG island methylation leads to increased CD137L expression, which promotes IL-8 production by MSI CRC cells. miRNA microarray; qRT-PCR; CpG methylation analysis; miR-484 overexpression/inhibition; CD137L expression measurement; IL-8 ELISA The Journal of pathology Medium 25727216
2017 CD137-CD137L signaling promotes vascular smooth muscle cell (VSMC) phenotype transformation from contractile to synthetic via NFATc1 activation. Recombinant CD137L upregulated NFATc1 expression; contractile phenotype markers (SM-MHC, α-SMA) decreased while synthetic marker (vimentin) and cell migration increased. These effects were blocked by anti-CD137 antibody or NFATc1 siRNA, and NFATc1 overexpression alone caused phenotype transformation. Recombinant CD137L stimulation; NFATc1 siRNA and lentiviral overexpression; Western blot; immunofluorescence; Transwell migration assay; in vivo neointima model Molecular and cellular biochemistry Medium 28770466
2024 4-1BBL expressed on Batf3-lineage dendritic cells within the tumor microenvironment is a major positive co-stimulatory signal for CD8+ T cell reinvigoration and tumor regression in response to PD-1/PD-L1 blockade. Blocking 4-1BBL or depleting Batf3+ DCs abrogated the efficacy of anti-PD-1 therapy. Gene-targeted mice (Batf3-/-); anti-4-1BBL blocking antibodies; flow cytometry; spatial transcriptomics on human tumor samples; tumor regression readout Cell reports Medium 38656869
2023 Macrophage STING signaling activates NLRP3-mediated IL-18 and IL-1β production, which promotes 4-1BBL expression on macrophages and 4-1BB expression on NK cells respectively, enabling 4-1BBL/4-1BB co-stimulation that enhances NK cell antitumor function against colorectal cancer liver metastasis. Global and myeloid-specific STING-/- mice; myeloid NLRP3-/- mice; NK cell depletion; bone marrow-derived macrophage/NK co-culture; flow cytometry; intrasplenic CRC mouse model Journal for immunotherapy of cancer Medium 36927529
2022 Galectin-3 (Gal-3) binds to both soluble and membrane-bound 4-1BB without blocking co-binding of 4-1BBL. Gal-3 forms large soluble 4-1BB/Gal-3 complexes (>100 nm) in plasma that attach to membrane 4-1BB on T cells, resulting in a ~4-fold decrease in TNFα production by 4-1BB+Gal-3+ T cells after 4-1BBL exposure, demonstrating Gal-3 suppresses 4-1BBL bioactivity by receptor clustering rather than direct competition. Co-binding assays; particle size analysis (plasma complexes); flow cytometry; TNFα production assay; 4-1BB-transfected HEK293 cells Frontiers in immunology Medium 35812455
2024 Hypoxia-induced lactic acid accumulation in glioma cells is absorbed by macrophages via MCT-1, leading to H3K18 lactylation (H3K18La) that epigenetically upregulates TNFSF9 expression. Elevated macrophage TNFSF9 then promotes M2 macrophage polarization and facilitates glioma progression. ChIP-seq identified H3K18La enrichment at the TNFSF9 locus. Silencing MCT-1 or the glycolysis inhibitor reversed TNFSF9 upregulation and M2 polarization. ChIP-seq for H3K18La; MCT-1 siRNA knockdown; glycolysis inhibitor; TNFSF9 knockdown; in vitro and in vivo glioma models American journal of physiology. Cell physiology Medium 39010835
2022 CD137L released by macrophages (stimulated by VEGF-C) binds to CD137 on lymphatic endothelial cells (LECs), activating PI3K/AKT/mTOR signaling that promotes autophagy (LC3-I to LC3-II conversion, Atg5, Atg7, Atg12 upregulation) and thereby enhances LEC proliferation, migration, and tube formation. Knockdown of Atg5 or Atg7 blocked CD137L-induced autophagy and lymphangiogenesis. Recombinant CD137L treatment of LECs; CD137 siRNA knockdown; Western blot (LC3, Atg proteins); PI3K/AKT/mTOR pathway analysis; Atg5/Atg7 siRNA; LEC proliferation/migration/tube formation assays; UUO mouse model International journal of biological sciences Medium 35173546
2012 SA-4-1BBL (oligomeric 4-1BBL) costimulation inhibits TGF-β- and antigen-driven conversion of naïve CD4+FoxP3- T cells into induced Tregs via stimulation of IFN-γ production by CD4+FoxP3- T cells. SA-4-1BBL also blocked conversion of CD4+ T cells into Tregs by EG.7 tumors in vivo. IFN-γ neutralization; in vitro iTreg conversion assay; in vivo tumor model with SA-4-1BBL treatment; FoxP3 expression analysis PloS one Medium 22870329

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Immune regulation by 4-1BB and 4-1BBL: complexities and challenges. Immunological reviews 251 19426223
2007 T cell-encoded CD80 and 4-1BBL induce auto- and transcostimulation, resulting in potent tumor rejection. Nature medicine 242 18026115
1999 Analysis of 4-1BB ligand (4-1BBL)-deficient mice and of mice lacking both 4-1BBL and CD28 reveals a role for 4-1BBL in skin allograft rejection and in the cytotoxic T cell response to influenza virus. Journal of immunology (Baltimore, Md. : 1950) 206 10528184
2014 Acute GVHD in patients receiving IL-15/4-1BBL activated NK cells following T-cell-depleted stem cell transplantation. Blood 203 25452614
2018 Structure of the 4-1BB/4-1BBL complex and distinct binding and functional properties of utomilumab and urelumab. Nature communications 121 30410017
2023 Macrophage STING signaling promotes NK cell to suppress colorectal cancer liver metastasis via 4-1BBL/4-1BB co-stimulation. Journal for immunotherapy of cancer 98 36927529
1999 4-1BBL cooperates with B7-1 and B7-2 in converting a B cell lymphoma cell line into a long-lasting antitumor vaccine. Journal of immunology (Baltimore, Md. : 1950) 97 10202049
2009 Therapeutic and tumor-specific immunity induced by combination of dendritic cells and oncolytic adenovirus expressing IL-12 and 4-1BBL. Molecular therapy : the journal of the American Society of Gene Therapy 95 19738604
2008 Prostaglandin E(2) enhances T-cell proliferation by inducing the costimulatory molecules OX40L, CD70, and 4-1BBL on dendritic cells. Blood 93 19029446
2007 Cell surface 4-1BBL mediates sequential signaling pathways 'downstream' of TLR and is required for sustained TNF production in macrophages. Nature immunology 91 17496895
2004 Costimulatory ligand 4-1BBL (CD137L) as an efficient adjuvant for human antiviral cytotoxic T cell responses. Proceedings of the National Academy of Sciences of the United States of America 83 14745033
2008 The capacity of the TNF family members 4-1BBL, OX40L, CD70, GITRL, CD30L and LIGHT to costimulate human T cells. European journal of immunology 80 18825741
2008 Identification of regulatory functions for 4-1BB and 4-1BBL in myelopoiesis and the development of dendritic cells. Nature immunology 77 18604213
2007 4-1BBL induces TNF receptor-associated factor 1-dependent Bim modulation in human T cells and is a critical component in the costimulation-dependent rescue of functionally impaired HIV-specific CD8 T cells. Journal of immunology (Baltimore, Md. : 1950) 69 18056369
2005 Evaluation of OX40 ligand as a costimulator of human antiviral memory CD8 T cell responses: comparison with B7.1 and 4-1BBL. Journal of immunology (Baltimore, Md. : 1950) 69 16272289
2021 Activation of 4-1BBL+ B cells with CD40 agonism and IFNγ elicits potent immunity against glioblastoma. The Journal of experimental medicine 66 32991668
2011 Reverse signaling through the costimulatory ligand CD137L in epithelial cells is essential for natural killer cell-mediated acute tissue inflammation. Proceedings of the National Academy of Sciences of the United States of America 65 22160719
2015 CD137 and CD137L signals are main drivers of type 1, cell-mediated immune responses. Oncoimmunology 62 27141396
2024 Intratumoral delivery of lipid nanoparticle-formulated mRNA encoding IL-21, IL-7, and 4-1BBL induces systemic anti-tumor immunity. Nature communications 59 39639025
2015 Hypoxia-induced soluble CD137 in malignant cells blocks CD137L-costimulation as an immune escape mechanism. Oncoimmunology 57 26942078
2007 Soluble PD-1 facilitates 4-1BBL-triggered antitumor immunity against murine H22 hepatocarcinoma in vivo. Clinical cancer research : an official journal of the American Association for Cancer Research 57 17325342
2024 Hypoxia conduces the glioma progression by inducing M2 macrophage polarization via elevating TNFSF9 level in a histone-lactylation-dependent manner. American journal of physiology. Cell physiology 53 39010835
2019 Recombinant Adenovirus Expressing a Soluble Fusion Protein PD-1/CD137L Subverts the Suppression of CD8+ T Cells in HCC. Molecular therapy : the journal of the American Society of Gene Therapy 50 31466933
2005 Cotransfection of dendritic cells with RNA coding for HER-2/neu and 4-1BBL increases the induction of tumor antigen specific cytotoxic T lymphocytes. Cancer gene therapy 50 15877082
2005 Production of recombinant human trimeric CD137L (4-1BBL). Cross-linking is essential to its T cell co-stimulation activity. The Journal of biological chemistry 50 16204238
2019 Autoinducer-2 of Fusobacterium nucleatum promotes macrophage M1 polarization via TNFSF9/IL-1β signaling. International immunopharmacology 45 31272064
2004 Expression of costimulatory molecules (4-1BBL and Fas) and major histocompatibility class I chain-related A (MICA) in aortic tissue with Takayasu's arteritis. Journal of vascular research 45 14752253
2014 Accumulation of 4-1BBL+ B cells in the elderly induces the generation of granzyme-B+ CD8+ T cells with potential antitumor activity. Blood 43 25037628
2011 Activating signals dominate inhibitory signals in CD137L/IL-15 activated natural killer cells. Journal of immunotherapy (Hagerstown, Md. : 1997) 43 21304401
2005 Enhancement of HIV-specific CD8 T cell responses by dual costimulation with CD80 and CD137L. Journal of immunology (Baltimore, Md. : 1950) 41 16272290
2009 A novel form of 4-1BBL has better immunomodulatory activity than an agonistic anti-4-1BB Ab without Ab-associated severe toxicity. Vaccine 40 19836479
2008 A novel antibody-4-1BBL fusion protein for targeted costimulation in cancer immunotherapy. Journal of immunotherapy (Hagerstown, Md. : 1997) 39 18779748
2020 Expanded clinical-grade membrane-bound IL-21/4-1BBL NK cell products exhibit activity against acute myeloid leukemia in vivo. European journal of immunology 38 32357256
2007 Targeted and untargeted CD137L fusion proteins for the immunotherapy of experimental solid tumors. Clinical cancer research : an official journal of the American Association for Cancer Research 38 17460060
2001 Expression of tumour necrosis factor (TNF) ligand superfamily co-stimulatory molecules CD30L, CD27L, OX40L, and 4-1BBL in murine hearts with acute myocarditis caused by Coxsackievirus B3. The Journal of pathology 38 11745696
2011 The combination of 4-1BBL and CD40L strongly enhances the capacity of dendritic cells to stimulate HIV-specific T cell responses. Journal of leukocyte biology 37 21427207
2009 A novel approach to induce human DCs from monocytes by triggering 4-1BBL reverse signaling. International immunology 36 19684160
2015 Methylation-induced loss of miR-484 in microsatellite-unstable colorectal cancer promotes both viability and IL-8 production via CD137L. The Journal of pathology 35 25727216
2014 SA-4-1BBL and monophosphoryl lipid A constitute an efficacious combination adjuvant for cancer vaccines. Cancer research 35 25252915
2006 Mantle cell lymphomas acquire increased expression of CCL4, CCL5 and 4-1BB-L implicated in cell survival. International journal of cancer 33 16287062
2017 Crystal structure of murine 4-1BB and its interaction with 4-1BBL support a role for galectin-9 in 4-1BB signaling. The Journal of biological chemistry 32 29242193
2012 SA-4-1BBL costimulation inhibits conversion of conventional CD4+ T cells into CD4+ FoxP3+ T regulatory cells by production of IFN-γ. PloS one 32 22870329
2008 Analysis of CD137 and CD137L expression in human primary tumor tissues. Croatian medical journal 31 18461674
2003 A functional anti-human 4-1BB ligand monoclonal antibody that enhances proliferation of monocytes by reverse signaling of 4-1BBL. Hybridoma and hybridomics 31 14678652
2022 4-1BBL-containing leukemic extracellular vesicles promote immunosuppressive effector regulatory T cells. Blood advances 30 35130345
2021 TNFSF9 promotes metastasis of pancreatic cancer through Wnt/Snail signaling and M2 polarization of macrophages. Aging 30 34517345
2019 CD137L-DCs, Potent Immune-Stimulators-History, Characteristics, and Perspectives. Frontiers in immunology 30 31632390
2018 Crystal structures of the human 4-1BB receptor bound to its ligand 4-1BBL reveal covalent receptor dimerization as a potential signaling amplifier. The Journal of biological chemistry 30 29720398
2012 Combination immunotherapy with 4-1BBL and CTLA-4 blockade for the treatment of prostate cancer. Clinical & developmental immunology 30 22312406
2012 4-1BB/4-1BBL interaction promotes obesity-induced adipose inflammation by triggering bidirectional inflammatory signaling in adipocytes/macrophages. Mediators of inflammation 30 23316108
2011 Long-term proliferation of functional human NK cells, with conversion of CD56(dim) NK cells to a CD56 (bright) phenotype, induced by carcinoma cells co-expressing 4-1BBL and IL-12. Cancer immunology, immunotherapy : CII 30 22021067
2004 Murine CD8 lymphocyte expansion in vitro by artificial antigen-presenting cells expressing CD137L (4-1BBL) is superior to CD28, and CD137L expressed on neuroblastoma expands CD8 tumour-reactive effector cells in vivo. Immunology 30 15096190
2021 TNFSF9 promotes metastasis of pancreatic cancer by regulating M2 polarization of macrophages through Src/FAK/p-Akt/IL-1β signaling. International immunopharmacology 29 34906856
2019 Autoinducer-2 of gut microbiota, a potential novel marker for human colorectal cancer, is associated with the activation of TNFSF9 signaling in macrophages. Oncoimmunology 29 31646072
2018 CD137L dendritic cells induce potent response against cancer-associated viruses and polarize human CD8+ T cells to Tc1 phenotype. Cancer immunology, immunotherapy : CII 29 29508025
2015 Expansion of NK cells from PBMCs using immobilized 4-1BBL and interleukin-21. International journal of oncology 29 25975533
2012 Recurrent deletions of the TNFSF7 and TNFSF9 genes in 19p13.3 in diffuse large B-cell and Burkitt lymphomas. International journal of cancer 29 22213068
2013 The TNF family member 4-1BBL sustains inflammation by interacting with TLR signaling components during late-phase activation. Science signaling 27 24084649
2013 Combining antibody-directed presentation of IL-15 and 4-1BBL in a trifunctional fusion protein for cancer immunotherapy. Molecular cancer therapeutics 27 24198185
2022 Inherited TNFSF9 deficiency causes broad Epstein-Barr virus infection with EBV+ smooth muscle tumors. The Journal of experimental medicine 25 35657354
2001 4-1BBL enhances anti-tumor responses in the presence or absence of CD28 but CD28 is required for protective immunity against parental tumors. Cellular immunology 25 11485353
2022 Role of TNFSF9 bidirectional signal transduction in antitumor immunotherapy. European journal of pharmacology 24 35714694
2012 Prime-boost vaccination with SA-4-1BBL costimulatory molecule and survivin eradicates lung carcinoma in CD8+ T and NK cell dependent manner. PloS one 24 23144888
2010 SA-4-1BBL as the immunomodulatory component of a HPV-16 E7 protein based vaccine shows robust therapeutic efficacy in a mouse cervical cancer model. Vaccine 24 20603135
2006 4-1BBL coexpression enhances HIV-specific CD8 T cell memory in a poxvirus prime-boost vaccine. Vaccine 24 17050052
2021 Dendritic cell therapy with CD137L-DC-EBV-VAX in locally recurrent or metastatic nasopharyngeal carcinoma is safe and confers clinical benefit. Cancer immunology, immunotherapy : CII 23 34661709
1997 Analysis of 4-1BBL and laminin binding to murine 4-1BB, a member of the tumor necrosis factor receptor superfamily, and comparison with human 4-1BB. The Journal of biological chemistry 23 9045669
2021 Intratumoral virotherapy with 4-1BBL armed modified vaccinia Ankara eradicates solid tumors and promotes protective immune memory. Journal for immunotherapy of cancer 21 33579736
2018 Crystal structure of the human 4-1BB/4-1BBL complex. The Journal of biological chemistry 21 29720399
2009 Adjuvantive effects of anti-4-1BB agonist Ab and 4-1BBL DNA for a HIV-1 Gag DNA vaccine: different effects on cellular and humoral immunity. Vaccine 21 19944789
2007 Blockade of the 4-1BB (CD137)/4-1BBL and/or CD28/CD80/CD86 costimulatory pathways promotes corneal allograft survival in mice. Immunology 21 17376197
2022 CD137L-macrophage induce lymphatic endothelial cells autophagy to promote lymphangiogenesis in renal fibrosis. International journal of biological sciences 20 35173546
2020 4-1BBL Regulates the Polarization of Macrophages, and Inhibition of 4-1BBL Signaling Alleviates Imiquimod-Induced Psoriasis. Journal of immunology (Baltimore, Md. : 1950) 20 32041783
2019 A DNA Vaccine Encoding SA-4-1BBL Fused to HPV-16 E7 Antigen Has Prophylactic and Therapeutic Efficacy in a Cervical Cancer Mouse Model. Cancers 20 30650588
2016 Gp96-Ig/Costimulator (OX40L, ICOSL, or 4-1BBL) Combination Vaccine Improves T-cell Priming and Enhances Immunity, Memory, and Tumor Elimination. Cancer immunology research 20 27364122
2006 Comparative analysis of antitumor activity of CD40L, RANKL, and 4-1BBL in vivo following intratumoral administration of viral vectors or transduced dendritic cells. The journal of gene medicine 20 16288496
2013 The TNF receptor-ligands 4-1BB-4-1BBL and GITR-GITRL in NK cell responses. Frontiers in immunology 19 23316193
2018 Crystal structure of the m4-1BB/4-1BBL complex reveals an unusual dimeric ligand that undergoes structural changes upon 4-1BB receptor binding. The Journal of biological chemistry 18 30545939
2017 CD137-CD137L interaction modulates neointima formation and the phenotype transformation of vascular smooth muscle cells via NFATc1 signaling. Molecular and cellular biochemistry 18 28770466
2014 HIV-1 adenoviral vector vaccines expressing multi-trimeric BAFF and 4-1BBL enhance T cell mediated anti-viral immunity. PloS one 18 24587225
2013 Recombinant Salmonella-based 4-1BBL vaccine enhances T cell immunity and inhibits the development of colorectal cancer in rats: in vivo effects of vaccine containing 4-1BBL. Journal of biomedical science 18 23413971
2010 Tumor cells engineered to codisplay on their surface 4-1BBL and LIGHT costimulatory proteins as a novel vaccine approach for cancer immunotherapy. Cancer gene therapy 18 20559332
2007 Adoptively transferred tumor-specific T cells stimulated ex vivo using herpes simplex virus amplicons encoding 4-1BBL persist in the host and show antitumor activity in vivo. Cancer research 18 17942937
2024 Batf3+ DCs and the 4-1BB/4-1BBL axis are required at the effector phase in the tumor microenvironment for PD-1/PD-L1 blockade efficacy. Cell reports 17 38656869
2020 An engineered 4-1BBL fusion protein with "activity on demand". Proceedings of the National Academy of Sciences of the United States of America 17 33239441
2017 TNFSF9 exerts an inhibitory effect on hepatocellular carcinoma. Journal of digestive diseases 17 28547807
2009 4-1BBL costimulation retrieves CD28 expression in activated T cells. Cellular immunology 17 19217084
2008 CD137L- and RANKL-mediated reverse signals inhibit osteoclastogenesis and T lymphocyte proliferation. Immunobiology 17 19167994
2006 Increased soluble 4-1BB ligand (4-1BBL) levels in peripheral blood of patients with multiple sclerosis. Scandinavian journal of immunology 17 16970683
2022 A Novel L-Phenylalanine Dipeptide Inhibits the Growth and Metastasis of Prostate Cancer Cells via Targeting DUSP1 and TNFSF9. International journal of molecular sciences 16 36142828
2019 A Novel Form of 4-1BBL Prevents Cancer Development via Nonspecific Activation of CD4+ T and Natural Killer Cells. Cancer research 16 30770367
2014 CD137-CD137L interaction regulates atherosclerosis via cyclophilin A in apolipoprotein E-deficient mice. PloS one 16 24520398
2010 Anti-tumor immune response induced by dendritic cells transduced with truncated PSMA IRES 4-1BBL recombinant adenoviruses. Cancer letters 16 20149524
2007 Neutralizing anti-4-1BBL treatment improves cardiac function in viral myocarditis. Laboratory investigation; a journal of technical methods and pathology 16 17468777
2002 Expression of tumor necrosis factor ligand superfamily costimulatory molecules CD27L, CD30L, OX40L and 4-1BBL in the heart of patients with acute myocarditis and dilated cardiomyopathy. Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology 16 12031769
2021 An Oncolytic Adenovirus Encoding SA-4-1BBL Adjuvant Fused to HPV-16 E7 Antigen Produces a Specific Antitumor Effect in a Cancer Mouse Model. Vaccines 15 33673295
2008 Induction of a VLA-2 (CD49b)-expressing effector T cell population by a cell-based neuroblastoma vaccine expressing CD137L. Journal of immunology (Baltimore, Md. : 1950) 15 18802064
2022 Galectin-3 Decreases 4-1BBL Bioactivity by Crosslinking Soluble and Membrane Expressed 4-1BB. Frontiers in immunology 14 35812455
2015 4-1BBL signaling promotes cell proliferation through reprogramming of glucose metabolism in monocytes/macrophages. The FEBS journal 14 25691217
2012 Reverse signaling through the co-stimulatory ligand, CD137L, as a critical mediator of sterile inflammation. Molecules and cells 14 22526397

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