TNFSF9
| TNFSF9 | |||||||||||||||||||||||||||||||||||||||||||||||
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| Aliases | TNFSF9 , 4-1BB-L, CD137L, TNLG5A, tumor necrosis factor superfamily member 9, TNF superfamily member 9 | ||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 606182; MGI: 1101058; HomoloGene: 55782; GeneCards: TNFSF9; OMA:TNFSF9 - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||
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Tumor necrosis factor ligand superfamily member 9 also known as 4-1BB ligand or 4-1BBL or CD137L is a protein that in humans is encoded by the TNFSF9 gene.[5]
4-1BBL is a type 2 transmembrane glycoprotein receptor that is found on APCs (antigen presenting cells) and binds to 4-1BB (also known as CD137). The 4-1BB/4-1BBL complex belongs to the TNFR:TNF superfamily,[6] which is expressed on activated T Lymphocytes.[7]
Structure
[edit ]TNFSF9 consists of an extracellular domain responsible for receptor binding, a transmembrane region, and a short intracellular domain, and can also exist in a soluble form when cleaved from the membrane. This structural organization enables TNFSF9 to function as a bidirectional signal transducer, facilitating costimulatory signaling crucial for T cell activation and immune response modulation.[8]
Receptor/ligand complex
[edit ]TNFSF9 forms a trimeric complex on the cell surface, which interacts with the 4-1BB (CD137) receptor on activated T lymphocytes. Each 4-1BB monomer binds to two 4-1BBL subunits via cysteine-rich domains (CRDs), with the CRD2 and CRD3 regions of 4-1BB engaging specific loops on 4-1BBL to stabilize the interaction through multiple hydrogen bonds.[8]
The 4-1BB/4-1BBL complex consists of three monomeric 4-1BBs bound to a trimeric 4-1BBL. Each 4-1BB monomer binds to two 4-1BBLs via cysteine-rich domains (CRDs). The interaction between 4-1BB and the second 4-1BBL is required to stabilize their interactions.[9] The link with 4-1BBL is largely made up of amino acids from the dynamic loops of the CRD2 and the β sheet of CRD3 of 4-1BB, according to a detailed study of the binding between the 4-1BB and 4-1BBL interface. CRD2 amino acids (T61, Q67, and K69) interact with the AA′ loop (Y110 and G114) and the intra-H-strand loop (Q227 and Q230) of 4-1BBL to form various hydrogen bond interactions.[10]
Function
[edit ]TNFSF9 plays a key role in immune cell interactions. TNFSF9 forms a trimeric complex on the cell surface, which interacts with the 4-1BB (CD137) receptor on activated T lymphocytes. Complex formation with its receptor enables TNFSF9 to function as a bidirectional signal transducer, facilitating costimulatory signaling crucial for T cell activation and immune response modulation.[8]
Clinical significance
[edit ]Early studies using the poorly immunogenic Ag104A sarcoma and highly tumorigenic P815 mastocytoma models provided the first systematic evidence that anti-4-1BB antibodies exert strong anti-tumor effects. These antibodies were found to significantly suppress tumor growth by enhancing cytotoxic T lymphocyte (CTL) activity. Subsequent research has consistently confirmed the role of 4-1BB signaling in promoting anti-tumor immunity.[11]
The 4-1BB/4-1BBL interaction delivers costimulatory signals that enhance T-cell responses, a mechanism with significant implications for cancer immunotherapy. When combined with T-cell receptor signaling, this interaction stimulates both CD4+ and CD8+ T cells, contributing to effective anti-tumor responses.[6] However, in human CD28− T cells, 4-1BB signaling can promote expansion of this subset, which is associated with adverse outcomes in cancer and other diseases. As a result, modulating this pathway represents a promising therapeutic strategy.[12]
See also
[edit ]References
[edit ]- ^ a b c GRCh38: Ensembl release 89: ENSG00000125657 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000035678 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ Singh R, Kim YH, Lee SJ, Eom HS, Choi BK (Feb 2024). "4-1BB immunotherapy: advances and hurdles". Experimental & Molecular Medicine. 56 (1): 32–39. doi:10.1038/s12276-023-01136-4. PMC 10834507 . PMID 38172595.
- ^ a b Cheuk AT, Mufti GJ, Guinn BA (March 2004). "Role of 4-1BB:4-1BB ligand in cancer immunotherapy". Cancer Gene Therapy. 11 (3): 215–226. doi:10.1038/sj.cgt.7700670. PMID 14671675. S2CID 11429744.
- ^ Lotze M (2001). Dendritic Cells. Boston: Academic Press. ISBN 978-0-12-455851-9.
- ^ a b c Choi BK, Lee HW (2020). "The Murine CD137/CD137 Ligand Signalosome: A Signal Platform Generating Signal Complexity". Frontiers in Immunology. 11 553715. doi:10.3389/fimmu.2020.553715 . PMC 7758191 . PMID 33362756.
- ^ Li Y, Tan S, Zhang C, Chai Y, He M, Zhang CW, et al. (October 2018). "Limited Cross-Linking of 4-1BB by 4-1BB Ligand and the Agonist Monoclonal Antibody Utomilumab". Cell Reports. 25 (4): 909–920.e4. doi:10.1016/j.celrep.2018年09月07日3 . PMID 30355497.
- ^ Li Y, Tan S, Zhang C, Chai Y, He M, Zhang CW, et al. (October 2018). "Limited Cross-Linking of 4-1BB by 4-1BB Ligand and the Agonist Monoclonal Antibody Utomilumab". Cell Reports. 25 (4): 909–920.e4. doi:10.1016/j.celrep.2018年09月07日3 . ISSN 2211-1247. PMID 30355497.
- ^ Vinay DS, Kwon BS (2012年05月01日). "Immunotherapy of Cancer with 4-1BB". Molecular Cancer Therapeutics. 11 (5): 1062–1070. doi:10.1158/1535-7163.MCT-11-0677 . ISSN 1535-7163. PMID 22532596.
- ^ Bukczynski J, Wen T, Watts TH (February 2003). "Costimulation of human CD28- T cells by 4-1BB ligand". European Journal of Immunology. 33 (2): 446–454. doi:10.1002/immu.200310020. PMID 12645943. S2CID 38395011.
External links
[edit ]- 4-1BB+Ligand at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
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