TNFSF9

TNFSF9
Identifiers
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
Available structures
PDB	Ortholog search: PDBe RCSB
List of PDB id codes
	2X29
Gene location (Human)
Chr.	Chromosome 19 (human)
End	6,535,924 bp
Gene location (Mouse)
Chr.	Chromosome 17 (mouse)
End	57,414,757 bp
RNA expression pattern
	Top expressed in
	buccal mucosa cell; ; testicle; ; internal globus pallidus; ; vagina; ; Brodmann area 9; ; right frontal lobe; ; upper lobe of left lung; ; prefrontal cortex; ; muscle of thigh; ; cerebellar hemisphere;
	Top expressed in
	gastrula; ; decidua; ; blastocyst; ; embryo; ; embryo; ; cumulus cell; ; humerus; ; ventricular zone; ; medial ganglionic eminence; ; stroma of bone marrow;
	More reference expression data
	n/a
Gene ontology
Molecular function	tumor necrosis factor receptor binding; cytokine activity; signaling receptor binding; tumor necrosis factor receptor superfamily binding;
Cellular component	integral component of membrane; membrane; extracellular space; plasma membrane;
Biological process	cell-cell signaling; cell population proliferation; immune response; signal transduction; apoptotic process; positive regulation of activated T cell proliferation; positive regulation of cytotoxic T cell differentiation; tumor necrosis factor-mediated signaling pathway; regulation of signaling receptor activity; regulation of T cell proliferation; regulation of apoptotic process;
	Sources:Amigo / QuickGO
Orthologs
	8744
	21950
	ENSG00000125657
	ENSMUSG00000035678
	P41273
	P41274
	NM_003811
	NM_009404
	NP_003802
	NP_033430
	Wikidata
View/Edit Human	View/Edit Mouse

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

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

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

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

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]

References

1 2 3 GRCh38: Ensembl release 89: ENSG00000125657 – Ensembl, May 2017
1 2 3 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.
1 2 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.
1 2 3 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.2018.09.073. 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.2018.09.073. ISSN 2211-1247. PMID 30355497.
↑ Vinay DS, Kwon BS (2012-05-01). "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

4-1BB+Ligand at the U.S. National Library of Medicine Medical Subject Headings (MeSH)

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[refGRCh38Ensembl-1] 1 2 3 GRCh38: Ensembl release 89: ENSG00000125657 – Ensembl, May 2017

[refGRCm38Ensembl-2] 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000035678 – Ensembl, May 2017

[3] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[Singh_2024-5] 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.

[Cheuk_2004-6] 1 2 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.

[7] Lotze M (2001). Dendritic Cells. Boston: Academic Press. ISBN 978-0-12-455851-9.

[Choi_2020-8] 1 2 3 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.

[9] 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.2018.09.073. PMID 30355497.

[10] 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.2018.09.073. ISSN 2211-1247. PMID 30355497.

[11] Vinay DS, Kwon BS (2012-05-01). "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.

[12] 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.

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