Affinage

TNFRSF9

Tumor necrosis factor receptor superfamily member 9 · UniProt Q07011

Length
255 aa
Mass
27.9 kDa
Annotated
2026-06-10
100 papers in source corpus 27 papers cited in narrative 27 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

TNFRSF9 (4-1BB/CD137) is an activation-inducible TNF receptor superfamily costimulatory receptor that amplifies T cell effector responses upon engagement of its ligand 4-1BBL (PMID:7678621, PMID:8088337, PMID:29720399). Lacking intrinsic enzymatic activity, the receptor signals through its cytoplasmic domain, where two runs of acidic residues recruit TRAF1, TRAF2, and TRAF3 to drive canonical NF-κB activation via a TRAF2/NIK axis (PMID:9464265), and all three TRAFs contribute to its costimulatory output (PMID:30232281). Productive signaling lowers the threshold for T cell activation in synergy with CD28, skews cytokines toward Th1 (notably IFN-γ), supports CD8+ T cell expansion and cytotoxicity, and reprograms metabolism by inducing OPA-1-dependent mitochondrial biogenesis and respiratory capacity (PMID:9541583, PMID:29678874, PMID:34911975). Costimulation delivered in cis (on the same cell as TCR-CD3 ligation) produces more intense canonical and non-canonical NF-κB signaling than trans engagement (PMID:34911975), and TCR-independent CD137 signaling drives proliferation and terminal differentiation of exhausted CD8+ T cells through RelA/cRel NF-κB and Tox-dependent chromatin remodeling (PMID:37392737). The receptor also acts beyond T cells: it is constitutively expressed on monocytes and signals bidirectionally to induce inflammatory cytokines and macrophage tumoricidal activity (PMID:9498794, PMID:10607752, PMID:34021248), and it is required for normal neutrophil microbicidal function (PMID:16041031). Biallelic loss-of-function mutations in TNFRSF9 abolish protein expression and cause defective CD8+ T cell expansion, cytotoxicity, and mitochondrial function, manifesting as failure to control EBV-infected T cells (chronic active EBV infection) (PMID:30872117, PMID:31537641). The receptor undergoes ADAM10-mediated ectodomain shedding to generate soluble CD137 (PMID:33800462), and within CAR-T constructs the 4-1BB domain can drive toxicity by TRAF-dependent sequestration of A20, producing NF-κB hyperactivity and RIPK1/RIPK3/MLKL necroptosis (PMID:28978471, PMID:38937625).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1993 High

    Established that 4-1BB is a cell-surface glycoprotein on T cells whose cross-linking costimulates proliferation, defining it as an accessory signaling molecule rather than a passive marker.

    Evidence mAb generation, SDS-PAGE/FACS biochemistry, and T cell proliferation assays with cross-linking

    PMID:7678621

    Open questions at the time
    • Ligand identity and binding affinity not yet defined
    • No intracellular signaling pathway identified
  2. 1994 High

    Quantified high-affinity 4-1BB/4-1BBL binding and showed signaling outcome is context-dependent, enhancing proliferation under mitogen but augmenting activation-induced cell death with TCR engagement.

    Evidence Cloning, Fc-fusion binding with Scatchard analysis, proliferation and cell death assays in primary T cells

    PMID:8088337

    Open questions at the time
    • Molecular basis of the proliferation-versus-death switch unresolved
    • Downstream signaling effectors not identified
  3. 1998 High

    Defined the proximal signaling mechanism, showing acidic cytoplasmic residues recruit TRAF1/2/3 to activate NF-κB through TRAF2/NIK, placing 4-1BB in the canonical TNFR signaling framework.

    Evidence Co-IP, cytoplasmic-domain mutagenesis, NF-κB reporter and dominant-negative TRAF2/NIK in Jurkat and 293 cells

    PMID:9464265

    Open questions at the time
    • Relative contributions of individual TRAFs not separated
    • Non-canonical NF-κB role not addressed
  4. 1998 Medium

    Extended 4-1BB function to costimulatory quality and beyond T cells, showing synergy with CD28, Th1 cytokine skewing, and bidirectional signaling that activates monocytes through a co-receptor on those cells.

    Evidence Intracellular cytokine staining, ELISA, and cross-linking with immobilized CD137 on primary monocytes

    PMID:9498794 PMID:9541583

    Open questions at the time
    • Monocyte counter-receptor for CD137 not molecularly identified
    • Bidirectional signaling components on monocytes undefined
  5. 2000 Medium

    Identified soluble CD137 as a delayed, potentially negative regulatory output correlating with reduced proliferation and increased activation-induced cell death.

    Evidence Time-course sCD137 ELISA correlated with proliferation and cell death readouts

    PMID:10607752 PMID:10843756

    Open questions at the time
    • No causal intervention demonstrating sCD137 function
    • Protease generating sCD137 not yet identified
  6. 2002 High

    Genetic loss-of-function in mice resolved the in vivo physiological role, showing 4-1BB is required for normal effector cytokine production and CTL activity while paradoxically restraining proliferation.

    Evidence 4-1BB knockout mice with proliferation, cytokine, CTL, and myeloid progenitor assays

    PMID:11867564 PMID:12023342

    Open questions at the time
    • Cell-type-specific contributions not dissected
    • Mechanism of proliferation restraint unexplained
  7. 2005 High

    Demonstrated a non-T-cell innate role, with 4-1BB required for neutrophil ROS production, phagocytosis, and calcium mobilization for bacterial clearance.

    Evidence 4-1BB KO mice in Listeria infection with ROS, phagocytosis, and Ca2+ assays plus agonist mAb

    PMID:16041031

    Open questions at the time
    • Neutrophil signaling pathway downstream of 4-1BB not defined
    • Ligand source in vivo not established
  8. 2010 High

    Showed 4-1BB shapes immune-compartment balance, with peripheral signaling driving IFN-γ that suppresses bone marrow NK development and shifts antitumor immunity toward CD8+ T cells.

    Evidence 4-1BB KO mice, tumor challenge, compartmental flow cytometry, IFN-γ neutralization

    PMID:15448685 PMID:20610645

    Open questions at the time
    • Direct versus indirect effects on NK progenitors not separated
    • IDO/IFN-γ regulatory circuit in other settings not generalized
  9. 2018 High

    Linked 4-1BB costimulation to metabolic reprogramming, establishing OPA-1-dependent mitochondrial biogenesis and respiratory capacity as required for antitumor T cell efficacy.

    Evidence MitoTracker, electron microscopy, OPA-1 knockout, oxygen consumption, and adoptive transfer tumor model

    PMID:29678874

    Open questions at the time
    • Signaling link from NF-κB to OPA-1 not mapped
    • Whether shedding regulates this metabolic program unknown
  10. 2018 High

    Resolved the structural basis of receptor-ligand engagement, showing 4-1BBL forms a canonical TNF-superfamily bell-shaped trimer, correcting an earlier propeller model.

    Evidence 2.4-Å X-ray crystallography of the 4-1BB/4-1BBL complex with interface mutagenesis

    PMID:29720399

    Open questions at the time
    • Stoichiometry of higher-order signaling clusters not defined
    • Conformational changes transmitting signal to cytoplasm not shown
  11. 2019 High

    Established human disease causality, with biallelic loss-of-function mutations abolishing CD137 expression and producing defective CD8+ T cell expansion, cytotoxicity, mitochondrial function, and failure to control EBV-infected T cells.

    Evidence Whole-exome sequencing, immunoblotting, cytotoxicity and mitochondrial assays, antibody recapitulation, and T cell expansion with CD137L-expressing cells

    PMID:30872117 PMID:31537641

    Open questions at the time
    • Tissue-specific consequences beyond T cells in patients not characterized
    • Genetic interaction with PIK3CD not fully separated in all cases
  12. 2017 Medium

    Revealed an epigenetic dimension to CD137 costimulation, showing agonist signaling reprograms genome-wide DNA methylation to alter immune-gene and transcription-factor expression.

    Evidence Genome-wide methylation arrays with pyrosequencing and mRNA/protein validation in human CD8+ T cells

    PMID:29133290

    Open questions at the time
    • Enzymes mediating methylation changes not identified
    • Causality between methylation and phenotype not fully demonstrated
  13. 2021 High

    Clarified signaling geometry and a defined shedding mechanism, showing cis costimulation outperforms trans and that ADAM10 mediates ectodomain shedding to generate soluble CD137 under phosphatidylserine-regulated control.

    Evidence Cis-versus-trans comparisons with NF-κB and mitochondrial assays; ADAM10 inhibitors and ANO6 overexpression with sCD137 ELISA

    PMID:33800462 PMID:34021248 PMID:34911975

    Open questions at the time
    • Physiological trigger of cis presentation in vivo not defined
    • Function of sCD137 generated by ADAM10 not causally tested
  14. 2023 High

    Identified a TCR-independent CD137 signaling program that drives proliferation and terminal differentiation of exhausted CD8+ T cells via RelA/cRel NF-κB and Tox-dependent chromatin remodeling.

    Evidence T cell-specific CD137 deletion, agonist treatment, NF-κB subunit analysis, and chromatin accessibility assays in mouse tumor models

    PMID:37392737

    Open questions at the time
    • Ligand source for TCR-independent signaling not defined
    • Reversibility of Tox-driven terminal differentiation unknown
  15. 2024 High

    Defined a toxicity mechanism intrinsic to 4-1BB-containing CAR constructs, where TRAF-dependent membrane sequestration of A20 causes NF-κB hyperactivity and RIPK1/RIPK3/MLKL necroptosis.

    Evidence TRAF-binding motif deletion, A20 overexpression rescue, Co-IP, NF-κB reporter, and necroptosis pathway analysis in CAR-T cells

    PMID:28978471 PMID:30232281 PMID:38937625

    Open questions at the time
    • Threshold of tonic signaling triggering necroptosis not quantified
    • Whether native 4-1BB engages A20 similarly not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the receptor's signaling outputs are switched between costimulatory survival, activation-induced death, metabolic reprogramming, and necroptotic toxicity by ligand geometry, TRAF stoichiometry, and shedding remains unresolved.
  • No unified model integrating cis/trans presentation with downstream effector choice
  • Counter-receptor mediating monocyte bidirectional signaling unidentified
  • Causal function of soluble CD137 in vivo undetermined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0048018 receptor ligand activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-5357801 Programmed Cell Death 1
Partners
ADAM10TNFAIP3TNFSF9TRAF1TRAF2TRAF3

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 4-1BB is a 30-kDa glycoprotein that exists as both a monomer and a 55-kDa dimer on the T cell surface; cross-linking of 4-1BB on anti-CD3-stimulated T cells dramatically enhanced T cell proliferation, demonstrating its function as an accessory costimulatory signaling molecule. mAb generation against recombinant soluble 4-1BB, SDS-PAGE, FACS analysis, T cell proliferation assay with cross-linking Journal of immunology High 7678621
1994 Human 4-1BB binds its ligand (4-1BBL) with high affinity (Scatchard analysis); ligation of 4-1BB on T cell clones enhanced activation-induced cell death when triggered alongside TCR/CD3 engagement, whereas mitogen co-stimulation induced strong proliferation. Molecular cloning, Fc-fusion protein binding assay, Scatchard analysis, proliferation and cell death assays European journal of immunology High 8088337
1998 Human 4-1BB signals are mediated through TRAF1, TRAF2, and TRAF3, which bind to two runs of acidic residues in the cytoplasmic domain of 4-1BB; 4-1BB cross-linking or overexpression activates NF-κB via a TRAF2/NIK pathway, as shown by dominant-negative TRAF2 and NIK inhibition. Co-immunoprecipitation, mutation analysis of cytoplasmic domain, NF-κB reporter assay in Jurkat and 293 cells, dominant-negative constructs Biochemical and biophysical research communications High 9464265
1998 4-1BB (CD137) signaling on monocytes induces expression of IL-6, IL-8, and TNF-α, inhibits IL-10, upregulates ICAM, and reduces FcγRIII expression; these effects require immobilized (cross-linked) CD137 protein, indicating they are mediated through a ligand/co-receptor on monocytes — establishing bidirectional signaling. Cytokine ELISA, flow cytometry for surface receptors, cross-linking assay with immobilized CD137 protein on primary human monocytes Journal of immunology Medium 9498794
1998 The 4-1BB signal synergized with CD28 co-stimulation to lower the threshold for T cell activation and IL-2 production; 4-1BB signaling skewed cytokine profiles toward Th1 (markedly enhanced IFN-γ) and suppressed Th2-type cytokines, preferentially in 4-1BB-expressing cells. T cell co-stimulation assays, intracellular cytokine staining for IFN-γ, cytokine ELISA, flow cytometry European journal of immunology Medium 9541583
2000 Soluble CD137 (sCD137) expression lags behind membrane-bound CD137 by ~24 h; sCD137 levels correlate negatively with lymphocyte proliferation and positively with activation-induced cell death, suggesting sCD137 may provide a negative regulatory mechanism for immune responses. Time-course analysis of sCD137 by ELISA, correlation with proliferation assay and activation-induced cell death Cytokine Medium 10843756
2000 CD137 is constitutively expressed on primary human monocytes; cross-linking of CD137 on monocytes induces IL-8 and TNF-α production, inhibits IL-10, and causes B lymphocyte apoptosis via direct cell–cell contact. Flow cytometry, ELISA for cytokines, cell–cell contact co-culture apoptosis assay International immunology Medium 10607752
2002 4-1BB-deficient mice develop normally but show enhanced T cell proliferation to mitogens/anti-CD3, reduced cytokine production (IL-2, IL-4), diminished CTL activity, and altered myeloid progenitor growth, indicating 4-1BB costimulation is required for normal T cell effector function but restrains proliferation. Genetic knockout mouse model, in vitro T cell proliferation assay, cytokine ELISA, CTL assay, bone marrow/spleen cell analysis Journal of immunology High 12023342
2002 4-1BBL is expressed on activated B cells, macrophages, and dendritic cells but not on T cells; 4-1BB is constitutively expressed on splenic dendritic cells and inducible on T cells; 4-1BBL stimulation of dendritic cells leads to IL-6 and IL-12 production and upregulation of co-stimulatory molecules. Flow cytometry with anti-4-1BB and anti-4-1BBL mAbs, co-culture experiments, cytokine ELISA International immunology Medium 11867564
2004 Anti-4-1BB agonist antibody treatment suppressed collagen-induced arthritis by inducing expansion of CD11c+CD8+ T cells; IFN-γ produced by these cells suppressed antigen-specific CD4+ T cells through an indoleamine 2,3-dioxygenase (IDO)-dependent mechanism, as shown by anti-IFN-γ and 1-methyltryptophan reversal. In vivo murine CIA model, antibody treatment, IDO inhibitor (1-methyltryptophan), anti-IFN-γ blocking, flow cytometry for T cell subsets Nature medicine High 15448685
2005 4-1BB (CD137) is required for rapid clearance of Listeria monocytogenes; 4-1BB-deficient mice showed impaired neutrophil reactive oxygen species generation, phagocytosis, and intracellular Ca2+ mobilization; 4-1BB ligation on neutrophils induced Ca2+ influx. 4-1BB KO mice, bacterial infection model, ROS assay, phagocytosis assay, Ca2+ influx measurement, anti-4-1BB mAb treatment Infection and immunity High 16041031
2010 4-1BB signaling in the periphery negatively regulates NK cell development through IFN-γ produced by peripheral CD8+ T and NK cells; this IFN-γ suppresses NK cell development in the bone marrow, shifting antitumor immunity from innate NK cell to adaptive CD8+ T cell dominance. 4-1BB KO mice, tumor challenge models, flow cytometry for NK cell frequency in spleen/bone marrow, IFN-γ neutralization Journal of immunology High 20610645
2017 Tonic 4-1BB signaling in CAR-T cells causes T cell toxicity via continuous TRAF2-dependent NF-κB activation and augmented FAS-dependent cell death; this was amplified by non-self-inactivating gammaretroviral vectors through positive feedback on the LTR promoter. CAR-T cell cultures, NF-κB reporter assay, TRAF2 knockdown, FAS pathway analysis, comparison of lentiviral vs. retroviral vectors Cell reports High 28978471
2018 4-1BB (CD137) costimulation induces mitochondrial enlargement, increasing mitochondrial mass and transmembrane potential in CD8+ T cells; this depends on mitochondrial fusion protein OPA-1 expression, enhances respiratory capacity, and is required for anti-tumor efficacy in adoptive T cell therapy. Mitochondrial staining (MitoTracker), transmission electron microscopy, OPA-1 knockout cells, oxygen consumption assay, in vivo adoptive transfer tumor model Cancer immunology research High 29678874
2018 4-1BB enhancement of CAR-T cell function is driven by NF-κB activation; TRAF1 and TRAF3 (in addition to TRAF2) are critical for 4-1BB costimulation in CAR-T cells, impacting viability, proliferation, cytotoxicity, and cytokine production. TRAF knockdown in CD19-CAR T cells, NF-κB reporter assay, cytotoxicity assay, cytokine ELISA, proliferation assay JCI insight High 30232281
2018 Activation of 4-1BB on liver myeloid cells (Kupffer cells and monocytes) is essential to initiate 4-1BB agonist-induced hepatitis; these cells produce IL-27 required for liver toxicity; CD8+ T cells then infiltrate and mediate tissue damage; FoxP3+ Tregs limit damage. Immunocompetent mice with KO for specific cytokines/chemokines, flow cytometry, serum transaminase measurement, in vivo depletion studies, CCR2-KO mice Clinical cancer research High 29301830
2018 The crystal structure of the human 4-1BB/4-1BBL complex at 2.4-Å resolution shows 4-1BBL forms a canonical bell-shaped trimer typical of TNF superfamily members (not the unusual three-bladed propeller reported previously); mutational data confirmed biological relevance of this structure. X-ray crystallography at 2.4-Å resolution, site-directed mutagenesis to validate interface The Journal of biological chemistry High 29720399
2019 CD137/4-1BB deficiency (homozygous biallelic loss-of-function mutation G109S abolishing protein expression) resulted in impaired CD8+ T cell expansion, reduced IFN-γ and perforin expression, diminished cytotoxicity against EBV-B cells, and significantly reduced mitochondrial biogenesis, membrane potential, and function in activated T cells. Whole-exome sequencing, immunoblotting, immunophenotyping, in vitro cytotoxicity assays, mitochondrial function assays, inhibitory antibody recapitulation experiments The Journal of allergy and clinical immunology High 30872117
2019 PIK3CD and TNFRSF9 (CD137) deficiency together cause chronic active EBV infection of T cells; isolated CD137 deficiency caused persistent EBV-infected T cells, demonstrating CD137 is specifically required for controlling EBV-infected T cell accumulation via T cell expansion through the CD137-CD137L pathway. Genetic sequencing identifying biallelic loss-of-function mutations, flow cytometry, in vitro T cell expansion assay with CD137L-expressing cells The Journal of experimental medicine High 31537641
2019 Oncogenic K-Ras upregulates CD137 in pancreatic cancer cells through activation of MAPK and NF-κB pathways, with NF-κB being mainly stimulated by K-Ras-induced IL-1α secretion that promotes CD137 gene transcription. Inducible K-RasG12V expression system, siRNA knockdown of MAPK1 and p65, RT-PCR, flow cytometry, ELISA Cancer communications Medium 31288851
2021 CD137 costimulation provided in cis (on the same cell as TCR-CD3 ligation) is superior to trans costimulation in terms of T cell activation, proliferation, survival, cytokine secretion, and mitochondrial fitness; cis CD137 ligation results in more intense canonical and non-canonical NF-κB signaling and stronger induction of cell cycle and DNA damage repair gene expression. Side-by-side comparison of cis vs. trans CD137 costimulation in vitro and in vivo, NF-κB signaling assays, gene expression profiling, mitochondrial fitness assays in mouse and human T cells Nature communications High 34911975
2021 CD137 stimulation enhances tumoricidal activity of human monocytes/macrophages through an ERK-dependent mechanism, inducing metabolic reprogramming and a functional skewing toward M1-like phenotype; CD137-high monocytes show increased antibody-dependent phagocytosis. Flow cytometry, transcriptomic analysis, ERK inhibition, phagocytosis assay, metabolic profiling of primary human monocytes Leukemia Medium 34021248
2021 ADAM10 (and potentially ADAM17) mediates ectodomain shedding of CD137 to generate soluble CD137 (sCD137); inhibition of ADAM10 uniformly blocked sCD137 release from transfected cell lines and primary T cells; phosphatidylserine exposure (controlled by ANO6 scramblase) modulates ADAM10-dependent shedding. ADAM10 inhibitors, ANO6 overexpression, sCD137 ELISA, primary T cell experiments International journal of molecular sciences Medium 33800462
2023 T cell-intrinsic, TCR-independent CD137 signaling stimulates proliferation and terminal differentiation of exhausted CD8+ T (Tex) precursor cells through RelA and cRel canonical NF-κB subunits and Tox-dependent chromatin remodeling. T cell-specific CD137 deletion (genetic KO), agonist antibody treatment, NF-κB subunit analysis (RelA, cRel), chromatin accessibility assay, flow cytometry for exhaustion markers in mouse tumor models Immunity High 37392737
2024 4-1BB incorporated within CAR constructs sequesters the ubiquitin-modifying enzyme A20 to the cell membrane in a TRAF-dependent manner, causing A20 functional deficiency that leads to NF-κB hyperactivity, ICAM-1 overexpression, cell aggregation, and cell death via RIPK1/RIPK3/MLKL necroptosis pathway; overexpressing A20 or deleting TRAF-binding motifs of 4-1BB rescued this phenotype. Mechanistic studies with A20 overexpression, deletion of TRAF-binding motifs in 4-1BB, co-immunoprecipitation, NF-κB reporter assay, RIPK1/RIPK3/MLKL pathway analysis, cell death and aggregation assays Cellular & molecular immunology High 38937625
2014 4-1BBL expressed on T cells can transmit reverse signals that limit T cell effector activity; cross-linking 4-1BBL inhibited IL-2 production, and APC-derived 4-1BB triggers 4-1BBL on T cells; T cell-intrinsic 4-1BB regulated internalization of membrane 4-1BBL, controlling the suppressive function of 4-1BBL. 4-1BBL-deficient T cell transfers, 4-1BB-deficient host experiments, in vitro cross-linking assay, Ab capture and endocytosis experiments, flow cytometry Journal of immunology Medium 25404362
2017 CD137 costimulation with agonist mAb (including urelumab) induces genome-wide DNA methylation changes in human CD8+ T cells, altering expression of immune-related genes including CD96, HHLA2, CCR5, CXCR5, and CCL5, as well as TCF1 transcription factor and miR-21 via methylation-dependent regulation. Genome-wide DNA methylation arrays, pyrosequencing validation, mRNA and protein expression analysis in human peripheral blood CD8+ T cells Cancer immunology research Medium 29133290

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors. Nature medicine 1471 25939063
2018 Enhancing CAR T cell persistence through ICOS and 4-1BB costimulation. JCI insight 469 29321369
2017 Immunotherapy targeting 4-1BB: mechanistic rationale, clinical results, and future strategies. Blood 383 29118009
1993 Inducible T cell antigen 4-1BB. Analysis of expression and function. Journal of immunology (Baltimore, Md. : 1950) 357 7678621
2021 A comparison of chimeric antigen receptors containing CD28 versus 4-1BB costimulatory domains. Nature reviews. Clinical oncology 307 34230645
2004 4-1BB-mediated immunotherapy of rheumatoid arthritis. Nature medicine 259 15448685
2009 Immune regulation by 4-1BB and 4-1BBL: complexities and challenges. Immunological reviews 251 19426223
1998 Role of 4-1BB in immune responses. Seminars in immunology 238 9826581
2010 Clinical experiences with anti-CD137 and anti-PD1 therapeutic antibodies. Seminars in oncology 230 21074066
2017 Tonic 4-1BB Costimulation in Chimeric Antigen Receptors Impedes T Cell Survival and Is Vector-Dependent. Cell reports 224 28978471
2002 Expression and function of 4-1BB and 4-1BB ligand on murine dendritic cells. International immunology 219 11867564
1994 Molecular and biological characterization of human 4-1BB and its ligand. European journal of immunology 216 8088337
2015 4-1BB Agonists: Multi-Potent Potentiators of Tumor Immunity. Frontiers in oncology 205 26106583
2003 Costimulation of T cells by OX40, 4-1BB, and CD27. Cytokine & growth factor reviews 188 12787564
2002 Immune responses in 4-1BB (CD137)-deficient mice. Journal of immunology (Baltimore, Md. : 1950) 172 12023342
1998 CD137 (ILA/4-1BB), a member of the TNF receptor family, induces monocyte activation via bidirectional signaling. Journal of immunology (Baltimore, Md. : 1950) 157 9498794
1998 Human 4-1BB (CD137) signals are mediated by TRAF2 and activate nuclear factor-kappa B. Biochemical and biophysical research communications 141 9464265
2012 Immunotherapy of cancer with 4-1BB. Molecular cancer therapeutics 140 22532596
2018 4-1BB enhancement of CAR T function requires NF-κB and TRAFs. JCI insight 136 30232281
2013 The TNFRs OX40, 4-1BB, and CD40 as targets for cancer immunotherapy. Current opinion in immunology 132 23414607
1995 ILA, the human 4-1BB homologue, is inducible in lymphoid and other cell lineages. Blood 127 7849293
2020 New emerging targets in cancer immunotherapy: CD137/4-1BB costimulatory axis. ESMO open 121 32611557
2019 Optimization of 4-1BB antibody for cancer immunotherapy by balancing agonistic strength with FcγR affinity. Nature communications 121 31105267
2011 4-1BB signaling beyond T cells. Cellular & molecular immunology 119 21217771
2015 Boosting Cancer Immunotherapy with Anti-CD137 Antibody Therapy. Clinical cancer research : an official journal of the American Association for Cancer Research 112 25908780
1998 Human 4-1BB regulates CD28 co-stimulation to promote Th1 cell responses. European journal of immunology 112 9541583
2010 CD137 (4-1BB) deficiency reduces atherosclerosis in hyperlipidemic mice. Circulation 109 20176988
2004 Role of 4-1BB:4-1BB ligand in cancer immunotherapy. Cancer gene therapy 108 14671675
2016 Deciphering CD137 (4-1BB) signaling in T-cell costimulation for translation into successful cancer immunotherapy. European journal of immunology 107 26773716
2014 4-1BB (CD137), an inducible costimulatory receptor, as a specific target for cancer therapy. BMB reports 107 24499671
2016 4-1BB agonism: adding the accelerator to cancer immunotherapy. Cancer immunology, immunotherapy : CII 102 27034234
2018 CD137 (4-1BB) Signalosome: Complexity Is a Matter of TRAFs. Frontiers in immunology 92 30524423
2008 The promise of 4-1BB (CD137)-mediated immunomodulation and the immunotherapy of cancer. Immunological reviews 91 18364008
2023 TCR-independent CD137 (4-1BB) signaling promotes CD8+-exhausted T cell proliferation and terminal differentiation. Immunity 90 37392737
2018 Activation of 4-1BB on Liver Myeloid Cells Triggers Hepatitis via an Interleukin-27-Dependent Pathway. Clinical cancer research : an official journal of the American Association for Cancer Research 85 29301830
2008 Multi-layered action mechanisms of CD137 (4-1BB)-targeted immunotherapies. Trends in pharmacological sciences 83 18599129
2019 Concomitant PIK3CD and TNFRSF9 deficiencies cause chronic active Epstein-Barr virus infection of T cells. The Journal of experimental medicine 80 31537641
2023 The emerging landscape of novel 4-1BB (CD137) agonistic drugs for cancer immunotherapy. mAbs 79 36727218
2018 Mitochondrial Morphological and Functional Reprogramming Following CD137 (4-1BB) Costimulation. Cancer immunology research 77 29678874
2019 Immunodeficiency and EBV-induced lymphoproliferation caused by 4-1BB deficiency. The Journal of allergy and clinical immunology 70 30872117
2000 Constitutive expression of functional 4-1BB (CD137) ligand on carcinoma cells. Journal of immunology (Baltimore, Md. : 1950) 70 10946324
2000 CD137 (ILA/4-1BB), expressed by primary human monocytes, induces monocyte activation and apoptosis of B lymphocytes. International immunology 69 10607752
2023 CD137 (4-1BB)-Based Cancer Immunotherapy on Its 25th Anniversary. Cancer discovery 68 36576322
2016 Rationale for anti-CD137 cancer immunotherapy. European journal of cancer (Oxford, England : 1990) 68 26751393
2019 An Update on Anti-CD137 Antibodies in Immunotherapies for Cancer. International journal of molecular sciences 67 31013788
2005 Interfacing T-cell effector and regulatory function through CD137 (4-1BB) co-stimulation. Trends in immunology 63 15979409
2004 Biological activities of reverse signal transduction through CD137 ligand. Journal of leukocyte biology 62 15618293
2025 Quercetin-Driven Akkermansia Muciniphila Alleviates Obesity by Modulating Bile Acid Metabolism via an ILA/m6A/CYP8B1 Signaling. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 60 39888270
2021 CD137 (4-1BB) costimulation of CD8+ T cells is more potent when provided in cis than in trans with respect to CD3-TCR stimulation. Nature communications 60 34911975
2021 Transient mTOR inhibition rescues 4-1BB CAR-Tregs from tonic signal-induced dysfunction. Nature communications 59 34750385
2020 Comprehensive analysis of tumor necrosis factor receptor TNFRSF9 (4-1BB) DNA methylation with regard to molecular and clinicopathological features, immune infiltrates, and response prediction to immunotherapy in melanoma. EBioMedicine 56 32028068
2015 A novel anti-GD2/4-1BB chimeric antigen receptor triggers neuroblastoma cell killing. Oncotarget 55 26298772
2024 4-1BB immunotherapy: advances and hurdles. Experimental & molecular medicine 54 38172595
2019 CD137 (4-1BB) Engagement Fine-Tunes Synergistic IL-15- and IL-21-Driven NK Cell Proliferation. Journal of immunology (Baltimore, Md. : 1950) 52 31201235
2006 Dual immunoregulatory pathways of 4-1BB signaling. Journal of molecular medicine (Berlin, Germany) 52 16924475
2000 Expression of soluble CD137 correlates with activation-induced cell death of lymphocytes. Cytokine 52 10843756
2009 CD137, implications in immunity and potential for therapy. Frontiers in bioscience (Landmark edition) 51 19273343
2000 4-1BB: still in the midst of darkness. Molecules and cells 51 10850651
2004 Anti-CD137 antibodies in the treatment of autoimmune disease and cancer. Immunologic research 50 15181282
2019 4-1BB Agonism Averts TIL Exhaustion and Licenses PD-1 Blockade in Glioblastoma and Other Intracranial Cancers. Clinical cancer research : an official journal of the American Association for Cancer Research 49 31871298
2005 Genetic and functional association of the immune signaling molecule 4-1BB (CD137/TNFRSF9) with type 1 diabetes. Journal of autoimmunity 49 15998581
2022 4-1BB: A promising target for cancer immunotherapy. Frontiers in oncology 46 36185242
2003 Blocking 4-1BB/4-1BB ligand interactions prevents herpetic stromal keratitis. Journal of immunology (Baltimore, Md. : 1950) 46 12847221
2020 Immunostimulatory oncolytic virotherapy for multiple myeloma targeting 4-1BB and/or CD40. Cancer gene therapy 44 32355275
2014 4-1BB chimeric antigen receptors. Cancer journal (Sudbury, Mass.) 44 24667959
2017 CD137 (4-1BB) Costimulation Modifies DNA Methylation in CD8+ T Cell-Relevant Genes. Cancer immunology research 41 29133290
1996 4-1BB is expressed on CD45RAhiROhi transitional T cell in humans. Cellular immunology 40 8612300
2003 Expression of CD137 and its ligand in human neurons, astrocytes, and microglia: modulation by FGF-2. Journal of neuroscience research 39 13130507
1995 Characterization of human homologue of 4-1BB and its ligand. Immunology letters 39 7622190
2021 CD137 (4-1BB) stimulation leads to metabolic and functional reprogramming of human monocytes/macrophages enhancing their tumoricidal activity. Leukemia 38 34021248
2005 4-1BB (CD137) is required for rapid clearance of Listeria monocytogenes infection. Infection and immunity 38 16041031
2014 4-1BB ligand signaling to T cells limits T cell activation. Journal of immunology (Baltimore, Md. : 1950) 37 25404362
2020 Differentiated agonistic antibody targeting CD137 eradicates large tumors without hepatotoxicity. JCI insight 36 32161196
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