ArticlePloS one2013
4-1BB signaling activates the t cell factor 1 effector/β-catenin pathway with delayed kinetics via ERK signaling and delayed PI3K/AKT activation to promote the proliferation of CD8+ T Cells.
Article in PloS one, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 53 citations in OpenAlex.
- FTL008.16, a 5T4-Conditional 4-1BB bispecific antibody, potently enhances antitumor immunity via tumor-directed t-cell activation.Oncoimmunology · 2026Article
- Generation of CCR4/CD7 Bispecific CAR-T Cells Resistant to Fratricide and Exhaustion.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- IRES-based RNAs expressing co-stimulatory molecules: Promising candidates for cancer immunotherapy.Molecular therapy. Nucleic acids · 2026Article
- OX40 signaling in cancer immunotherapy: mechanisms of action, translational applications, and therapeutic perspectives.Frontiers in immunology · 2026Review
- Chimeric CD3ζ chains containing CD28 signalling motifs enhance antigen-specific IL-2 production and expansion of human TCR-engineered T cellsImmunotherapy advances · 2026Article
- Discordant CAR-T cell signaling: implications of divergence from physiological T cell activation.Journal of translational medicine · 2025Review
- MD Simulation Reveals a Trimerization-Enhanced Interaction of CD137L with CD137.International journal of molecular sciences · 2025Article
- A mechanistic quantitative systems pharmacology model platform for translational efficacy evaluation and checkpoint combination design of bispecific immuno-modulatory antibodies.Frontiers in pharmacology · 2025Article
- Clinical and functional characterization of a novelFrontiers in immunology · 2025Article
- Article
- Engineered soluble, trimerized 4-1BBL variants as potent immunomodulatory agents.Cancer immunology, immunotherapy : CII · 2023Article
- Targeting CD137 (4-1BB) towards improved safety and efficacy for cancer immunotherapy.Frontiers in immunology · 2023Review
- CD137 (4-1BB) costimulation of CD8Nature communications · 2021Article
- The Interplay Between Epigenetic Regulation and CD8Frontiers in cell and developmental biology · 2021Review
- A Prospective Investigation of Bispecific CD19/22 CAR T Cell Therapy in Patients With Relapsed or Refractory B Cell Non-Hodgkin Lymphoma.Frontiers in oncology · 2021Article
- A Fas-4-1BB fusion protein converts a death to a pro-survival signal and enhances T cell therapy.The Journal of experimental medicine · 2020Article
- 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 · 2020Article
- Induction of NKG2D ligand expression on tumor cells by CD8Oncogene · 2019Article
- Quercetin prevents small intestinal damage and enhances intestinal recovery during methotrexate-induced intestinal mucositis of rats.Food & nutrition research · 2018Article
- CD137 (4-1BB) Signalosome: Complexity Is a Matter of TRAFs.Frontiers in immunology · 2018Review
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
4-1BB (CD137), an inducible costimulatory molecule, strongly enhances the proliferation and effector function of CD8(+) T cells. Since the serine/threonine kinase, glycogen synthase kinase-3 (GSK-3), is involved in a variety of signaling pathways of cellular proliferation, migration, immune responses, and apoptosis, we examined whether 4-1BB signaling activates GSK-3/β-catenin signaling and downstream transcription factors to enhance the proliferation of CD8(+) T cells. 4-1BB signaling induces rapid activation of ERK and IκB degradation, and shows delayed activation of AKT at 24 h post 4-1BB stimulation on anti-CD3 activated T cells. ERK and AKT signals were required for sustained β-catenin levels by inactivating GSK-3, which was also observed with delayed kinetics after 4-1BB stimulation. As a transcriptional partner of β-catenin, 4-1BB signaling decreased levels of FOXO1 and increased levels of stimulatory TCF1 in CD8(+) T cells at 2-3 days but not at early time points after 4-1BB engagement. The enhanced proliferation of CD8(+) T cells due to 4-1BB signaling was completely abolished by treatment with the TCF1/β-catenin inhibitor quercetin. These results show that 4-1BB signaling enhances the proliferation of activated CD8(+) T cells by activating the TCF1/β-catenin axis via the PI3K/AKT/ERK pathway. As effects of 4-1BB on AKT, FOXO1, β-catenin and GSK-3β showed delayed kinetics it is likely that an intervening molecule induced by 4-1BB and ERK signaling in activated T cells is responsible for these effects. These effects were observed on CD8(+) but not on CD4(+) T cells. Moreover, 4-1BB appeared to be unique among several TNFRs tested in inducing increase in stimulatory over inhibitory TCF-1.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.