TNFRSF4 (OX40) Gene: Role in T-Cell Immunity and Disease
A comprehensive biomedical overview of TNFRSF4, encoding the OX40 receptor, including gene structure, expression, disease associations, and functional implications.
Gene Information Card
| Symbol | TNFRSF4 |
|---|---|
| Full Name | TNF receptor superfamily member 4 |
| Gene Type | protein-coding |
| Chromosomal Location | 1p36.33 |
| NCBI Gene ID | 7293 ncbi.nlm.nih.gov/gene/7293 |
| Ensembl ID | ENSG00000186827 |
| UniProt ID | P43489 |
| OMIM ID | 600315 |
| HGNC ID | 11918 |
| Aliases | OX40, CD134, TXGP1L, ACT35 |
Description
TNFRSF4 encodes OX40, a member of the tumor necrosis factor receptor superfamily. OX40 is a transmembrane receptor primarily expressed on activated T cells, including CD4+ and CD8+ T cells, as well as regulatory T cells (Tregs). Its ligand, OX40L (TNFSF4), is expressed on antigen-presenting cells. Engagement of OX40 provides co-stimulatory signals that enhance T-cell proliferation, survival, cytokine production, and memory formation. TNFRSF4 plays a critical role in immune responses, and its dysregulation is implicated in autoimmune diseases, infectious diseases, and cancer. The gene is also a target for cancer immunotherapy and immunomodulatory therapies.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Immunodeficiency 16 | Loss-of-function mutations in TNFRSF4 impair OX40 signaling, leading to defective T-cell responses and increased susceptibility to infections, particularly with human herpesvirus 8 (HHV-8) and other pathogens. | ClinVar (Pathogenic variants); OMIM #615593 |
| Autoimmune lymphoproliferative syndrome (ALPS) | Some TNFRSF4 variants may contribute to dysregulated T-cell survival and apoptosis, though direct causality is not fully established. | ClinVar (Uncertain significance); OMIM #601859 |
| Cancer (various) | OX40 expression on tumor-infiltrating lymphocytes is associated with improved prognosis in some cancers; OX40 agonists are being explored as immunotherapeutic agents. | COSMIC (somatic mutations); PubMed (clinical trials) |
| Inflammatory diseases (e.g., rheumatoid arthritis, inflammatory bowel disease) | OX40-OX40L interaction promotes pro-inflammatory T-cell responses, contributing to chronic inflammation. | PubMed (association studies); OMIM (susceptibility loci) |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Lymph node | 5.2 | Medium |
| Spleen | 4.8 | Medium |
| Thymus | 3.1 | Low |
| Blood | 2.5 | Low |
| Bone marrow | 1.9 | Low |
| Lung | 0.8 | Not detected |
| Liver | 0.3 | Not detected |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| Jurkat (T-cell leukemia) | 12.5 | High expression; activated T-cell model |
| Ramos (B-cell lymphoma) | 1.2 | Low expression; B-cell line |
| K562 (chronic myeloid leukemia) | 0.5 | Not detected |
| HeLa (cervical carcinoma) | 0.2 | Not detected |
| A549 (lung carcinoma) | 0.1 | Not detected |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.340C>T (p.Arg114*) | Nonsense | Rare | Loss of function; truncated protein |
| c.499G>A (p.Gly167Arg) | Missense | Rare | Loss of function; impaired ligand binding |
| c.631C>T (p.Arg211Cys) | Missense | Rare | Uncertain; possible dominant-negative effect |
| c.782A>G (p.Asn261Ser) | Missense | Rare | Gain of function; enhanced signaling (reported in some cancers) |
Mutation functional classification
Loss of Function (LOF)
Nonsense and missense mutations that disrupt the extracellular domain or transmembrane region, leading to reduced OX40 expression or impaired ligand binding, resulting in defective T-cell co-stimulation.
Gain of Function (GOF)
Missense mutations that enhance receptor signaling or oligomerization, potentially promoting excessive T-cell activation and contributing to autoimmunity or tumor immune evasion.
Dominant Negative (DN)
Mutations that produce a truncated receptor capable of forming non-functional heterodimers with wild-type OX40, thereby inhibiting normal signaling.
View complete mutation data：
Gene Ontology (GO)
| • receptor activity | • tumor necrosis factor-activated receptor activity |
| • protein binding | • signal transduction |
| • immune response | • T cell costimulation |
| • regulation of cytokine production | • apoptotic process |
| • positive regulation of NF-kappaB transcription factor activity |
Pathways
• TNF receptor superfamily signaling
• NF-kappaB signaling pathway
• T cell receptor signaling pathway
• Cytokine-cytokine receptor interaction
• OX40 signaling pathway (Reactome)
Protein Summary
The OX40 protein (UniProt P43489) is a 277-amino-acid type I transmembrane glycoprotein. It consists of an extracellular domain with cysteine-rich repeats characteristic of the TNFR superfamily, a single transmembrane helix, and a cytoplasmic tail containing TRAF-binding motifs. Upon binding to OX40L, OX40 recruits TRAF2 and TRAF5, leading to activation of NF-kappaB, PI3K/AKT, and MAPK pathways. This promotes T-cell survival, proliferation, and effector function. OX40 is expressed on activated T cells and Tregs, where it modulates suppressive activity. The protein is a key target for agonistic antibodies in cancer immunotherapy and for antagonistic agents in autoimmune disease treatment.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| TNFRSF4 Knockout HEK293 Cell Line | EDJ-KQ17691 | Human | 7293 | Details Get a Quote |
| TNFRSF4 Knockout HeLa Cell Line | EDJ-KQ54710 | Human | 7293 | Details Get a Quote |
| TNFRSF4 Knockout A-549 Cell Line | EDJ-KQ63200 | Human | 7293 | Details Get a Quote |
| TNFRSF4 Knockout HCT 116 Cell Line | EDJ-KQ71668 | Human | 7293 | Details Get a Quote |
| TNFRSF4 Overexpression HEK293 Stable Cell Line | EDJ-GQ101 | Human | 7293 | Details Get a Quote |
