TNFSF9 (4-1BB Ligand): A Costimulatory Immune Checkpoint Gene
Explore the genomic context, expression, and clinical relevance of TNFSF9, a key regulator of T-cell immunity and a promising therapeutic target.
Gene Information Card
| Symbol | TNFSF9 |
|---|---|
| Full Name | Tumor Necrosis Factor Superfamily Member 9 |
| Gene Type | Protein coding |
| Chromosomal Location | 19p13.3 |
| NCBI Gene ID | 8744 ncbi.nlm.nih.gov/gene/8744 |
| Ensembl ID | ENSG00000125657 |
| UniProt ID | P41273 |
| OMIM ID | 606182 |
| HGNC ID | 11939 |
| Aliases | 4-1BB-L, CD137L, TNLG8A |
Description
TNFSF9 encodes 4-1BB ligand (4-1BBL), a type II transmembrane protein belonging to the tumor necrosis factor (TNF) superfamily. It is expressed on antigen-presenting cells (APCs) such as dendritic cells, macrophages, and B cells, and binds to its receptor 4-1BB (CD137, TNFRSF9) on T cells. This interaction provides a costimulatory signal that enhances T-cell proliferation, survival, and cytokine production, playing a critical role in immune responses and antitumor immunity.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Cancer (various) | TNFSF9 expression on tumor cells or APCs can modulate antitumor immunity; agonistic anti-4-1BB antibodies are being tested in clinical trials. | Clinical trials (e.g., NCT01307267) and preclinical studies. |
| Autoimmune diseases | Enhanced 4-1BB/4-1BBL signaling may exacerbate inflammatory responses, contributing to autoimmune pathology. | Studies in animal models (e.g., EAE) and human genetic associations. |
| Viral infections | TNFSF9 costimulation is involved in antiviral T-cell responses; dysregulation may affect viral clearance. | Research on chronic viral infections (e.g., HIV, LCMV). |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Lymph node | High | High expression in secondary lymphoid organs. |
| Spleen | High | High expression in splenic APCs. |
| Bone marrow | Medium | Present on hematopoietic progenitors. |
| Peripheral blood | Medium | Expressed on monocytes and B cells. |
| Liver | Low | Low expression in hepatocytes. |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| Dendritic cells (immature) | High | Constitutively expressed; upregulated upon maturation. |
| Macrophages (M1) | High | Pro-inflammatory macrophages express high levels. |
| B cells (activated) | Medium | Upregulated after activation. |
| T cells (resting) | Low | Not expressed on resting T cells; induced upon activation. |
| Tumor cell lines (e.g., melanoma) | Variable | Some tumors express TNFSF9, potentially modulating immune escape. |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.416C>T (p.Pro139Leu) | Missense | Rare (<0.1%) | Unknown; may affect protein stability. |
| c.582G>A (p.Thr194Thr) | Synonymous | Rare | No functional effect. |
| c.1-18C>T | 5' UTR variant | Rare | Potential effect on translation efficiency. |
Mutation functional classification
Loss of Function (LOF)
No well-characterized loss-of-function mutations reported in TNFSF9; gene knockout in mice impairs T-cell responses.
Gain of Function (GOF)
No gain-of-function mutations described; overexpression in tumors may contribute to immune evasion.
Dominant Negative (DN)
Not applicable; TNFSF9 functions as a trimer, but no dominant-negative variants have been identified.
View complete mutation data：
Gene Ontology (GO)
| • tumor necrosis factor receptor binding | • cytokine activity |
| • protein homodimerization activity | • signal transduction |
| • immune response | • positive regulation of T cell proliferation |
| • positive regulation of cytokine production | • cell surface receptor signaling pathway |
Pathways
• TNF signaling pathway (KEGG hsa04668)
• T cell receptor signaling pathway (KEGG hsa04660)
• Cytokine-cytokine receptor interaction (KEGG hsa04060)
• 4-1BB-mediated NF-kB activation (Reactome: R-HSA-5676590)
Protein Summary
The TNFSF9 protein (4-1BBL) is a 254-amino acid type II transmembrane protein with a C-terminal extracellular TNF homology domain. It forms homotrimers and binds to 4-1BB (CD137) on T cells, triggering TRAF2/NF-kB signaling that promotes T-cell survival and memory formation. Soluble forms of 4-1BBL exist and may have distinct functions. The protein is a target for cancer immunotherapy, with agonistic antibodies and recombinant ligands being explored.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| TNFSF9 Knockout HEK293 Cell Line | EDJ-KQ2815 | Human | 8744 | Details Get a Quote |
| TNFSF9 Knockout A-549 Cell Line | EDJ-KQ22404 | Human | 8744 | Details Get a Quote |
| TNFSF9 Knockout HCT 116 Cell Line | EDJ-KQ23774 | Human | 8744 | Details Get a Quote |
| TNFSF9 Knockout HeLa Cell Line | EDJ-KQ23775 | Human | 8744 | Details Get a Quote |
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