ReviewJournal of molecular medicine (Berlin, Germany)2006
Dual immunoregulatory pathways of 4-1BB signaling.
Review in Journal of molecular medicine (Berlin, Germany), 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 58 citations in OpenAlex.
- Astrocytes in Multiple Sclerosis: Getting to the Core.International journal of molecular sciences · 2026Review
- Spatial protein profiling reveals active roles for astrocytes in the chronic active lesion core during multiple sclerosis.Acta neuropathologica · 2025Article
- The 41BB-agonist potentiates the therapeutic efficacy of a combined irreversible electroporation ablation treatment of lung cancer by promoting unexpected CD8Frontiers in immunology · 2025Article
- CAR-T cell potency: from structural elements to vector backbone components.Biomarker research · 2022Review
- Immune profiles in mouse brain and testes infected by Zika virus with variable pathogenicity.Frontiers in cellular and infection microbiology · 2022Article
- 4-1BB: A promising target for cancer immunotherapy.Frontiers in oncology · 2022Review
- CD73 immune checkpoint defines regulatory NK cells within the tumor microenvironment.The Journal of clinical investigation · 2020Article
- Article
- Targeting the 4-1BB costimulatory molecule through single chain antibodies promotes the human T-cell response.Cellular & molecular biology letters · 2020Article
- 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 · 2018Article
- Regulatory T Cell-Mediated Suppression of Inflammation Induced by DR3 Signaling Is Dependent on Galectin-9.Journal of immunology (Baltimore, Md. : 1950) · 2017Article
- Immune Checkpoint Modulators: An Emerging Antiglioma Armamentarium.Journal of immunology research · 2016Review
- The pharmacology of second-generation chimeric antigen receptors.Nature reviews. Drug discovery · 2015Review
- Botulinum neurotoxin type A induces TLR2-mediated inflammatory responses in macrophages.PloS one · 2015Article
- Targeting 4-1BB costimulation to the tumor stroma with bispecific aptamer conjugates enhances the therapeutic index of tumor immunotherapy.Cancer immunology research · 2014Article
- Targeting CD137 enhances vaccine-elicited anti-respiratory syncytial virus CD8+ T cell responses in aged mice.Journal of immunology (Baltimore, Md. : 1950) · 2014Article
- Human and mouse CD137 have predominantly different binding CRDs to their respective ligands.PloS one · 2014Article
- Targeting of 4-1BB by monoclonal antibody PF-05082566 enhances T-cell function and promotes anti-tumor activity.Cancer immunology, immunotherapy : CII · 2012Article
- CD137 differentially regulates innate and adaptive immunity against Mycobacterium tuberculosis.Immunology and cell biology · 2012Article
- Article
Corrections and comments
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Authors and funding
3 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
It is perhaps rare to encounter among the various immunologically competent receptor-ligand pairs that a single cell surface determinant unleashes both a hidden suppressive function and costimulation. 4-1BB, an activation-induced tumor necrosis factor receptor family member chiefly viewed as a powerful T-cell costimulatory molecule, is one such example. Accumulated evidence in recent years uncovered an unknown facet of in vivo 4-1BB signaling (i.e., "active suppression"). Although in vitro signaling via 4-1BB is shown to support both CD4(+) and CD8(+) T-cell responses, the same induces a predominant CD8(+) T-cell response suppressing CD4(+) T-cell function when applied in vivo. How, when, and why such dual immunoregulatory effect of anti-4-1BB monoclonal antibody (MAB) comes into play is currently the focus of intense research. Existing data, although not complete, uncover several important aspects of in vivo 4-1BB signaling in the amelioration or exacerbation of various immune disorders. Despite minor disagreements, a majority agree that upregulation of interferon (IFN)-gamma is critical to anti-4-1BB MAB therapy in addition to immune modulators such as interleukin 2, transforming growth factor beta, and indolamine 2,3-dioxygenase(5), all of which contribute greatly to the success of anti-4-1BB MAB-based immunotherapy. Anti-4-1BB MAB-mediated expansion of novel CD11c(+)CD8(+) T cells is additional weaponry that appears critical for its in vivo suppressive function. These CD11c(+)CD8(+) T cells express high levels of IFN-gamma, become effective killers, and mediate selective suppression of CD4(+) T cells. In this review, we discuss the dual nature (costimulatory and suppressive) of 4-1BB-mediated immune regulation, its current status, future direction, and its impact on the immune system, with special reference to its immunotherapy.
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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.