TNFSF9

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.{{cite journal | vauthors = Choi BK, Lee HW | title = The Murine CD137/CD137 Ligand Signalosome: A Signal Platform Generating Signal Complexity | journal = Frontiers in Immunology | volume = 11 | issue = | pages = 553715 | date = 2020 | pmid = 33362756 | pmc = 7758191 | doi = 10.3389/fimmu.2020.553715 | doi-access = free | url = }}

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.

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.{{cite journal | vauthors = Li Y, Tan S, Zhang C, Chai Y, He M, Zhang CW, Wang Q, Tong Z, Liu K, Lei Y, Liu WJ, Liu Y, Tian Z, Cao X, Yan J, Qi J, Tien P, Gao S, Gao GF | title = Limited Cross-Linking of 4-1BB by 4-1BB Ligand and the Agonist Monoclonal Antibody Utomilumab | journal = Cell Reports | volume = 25 | issue = 4 | pages = 909–920.e4 | date = October 2018 | pmid = 30355497 | doi = 10.1016/j.celrep.2018.09.073 | doi-access = free }} 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.{{Cite journal | vauthors = Li Y, Tan S, Zhang C, Chai Y, He M, Zhang CW, Wang Q, Tong Z, Liu K, Lei Y, Liu WJ | title = Limited Cross-Linking of 4-1BB by 4-1BB Ligand and the Agonist Monoclonal Antibody Utomilumab | journal = Cell Reports | volume = 25 | issue = 4 | pages = 909–920.e4 | date = October 2018 | pmid = 30355497 | doi = 10.1016/j.celrep.2018.09.073 | issn = 2211-1247 | doi-access = free }}

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.

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.{{Cite journal | vauthors = Vinay DS, Kwon BS | title = Immunotherapy of Cancer with 4-1BB | journal = Molecular Cancer Therapeutics | volume = 11 | issue = 5 | pages = 1062–1070 | date = 2012-05-01 | pmid = 22532596 | doi = 10.1158/1535-7163.MCT-11-0677 | language = en | issn = 1535-7163 | doi-access = free }}

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. 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.{{cite journal | vauthors = Bukczynski J, Wen T, Watts TH | title = Costimulation of human CD28- T cells by 4-1BB ligand | journal = European Journal of Immunology | volume = 33 | issue = 2 | pages = 446–454 | date = February 2003 | pmid = 12645943 | doi = 10.1002/immu.200310020 | s2cid = 38395011 }}

• CD137

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• {{MeshName|4-1BB+Ligand}}

{{Glycoproteins}}

{{Tumor necrosis factors}}

{{Cytokine receptor modulators}}

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