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GeneE
26 sources retrieved · Most recent: April 2026 · Index updated 15 days ago
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TNFSF4
TNF superfamily member 4
Chromosome 1 · 1q25.1
NCBI Gene: 7292Ensembl: ENSG00000117586.13HGNC: HGNC:11934UniProt: A0A024R937
167PubMed Papers
21Diseases
2Drugs
0Pathogenic Variants
RESEARCH IMPACT
Trending
CLINICAL
Clinical TrialsOMIM Disease Gene
DATA QUALITY
✓ Experimental GO Evidence✓ Swiss-Prot Reviewed
GO:0005615cellular response to lipopolysaccharidepositive regulation of inflammatory responsepositive regulation of interleukin-6 productionsystemic lupus erythematosusasthmaatopic eczemaallergic rhinitis
✦AI Summary

TNFSF4 encodes OX40 ligand (OX40L), a TNF superfamily cytokine that binds to TNFRSF4 (OX40 receptor) and functions as a T-cell costimulatory molecule 1. OX40L is expressed on antigen-presenting cells, activated T cells, and other cell types; expression increases after antigen presentation and in response to pro-inflammatory signals including CD28 ligation and interferon-gamma 1. The OX40-OX40L interaction promotes T-cell survival, effector T-cell differentiation, T-cell memory formation, and increased effector cytokine production, while reducing regulatory T-cell function 12. TNFSF4 is implicated in multiple autoimmune and inflammatory conditions. Genetic variants in TNFSF4 associate with systemic lupus erythematosus and IgA nephropathy, positioning it within inflammatory signaling pathways 3. In atopic dermatitis, increased OX40L expression on antigen-presenting cells drives pathogenic T-cell proliferation across Th2, Th1, Th17, and Th22 subsets, contributing to chr1 inflammation 45. Cell-cell communication studies reveal elevated TNFSF4-TNFRSF4 interactions in thyroid-associated ophthalmopathy and esophageal squamous cell carcinoma, suggesting broader disease relevance 67. Therapeutic blockade of OX40L represents a promising strategy for treating autoimmune and inflammatory diseases.

Sources cited
1
OX40L is the cognate ligand for OX40; expressed on APCs and activated T cells; expression increases after antigen presentation and pro-inflammatory signals; promotes T-cell survival, effector phenotype, and memory while reducing regulatory function
PMID: 26215166
2
OX40L (TNFSF4) expression is increased in atopic dermatitis; OX40 pathway critical for T-cell expansion, differentiation, and survival; blocking OX40L is therapeutic target
PMID: 38236520
3
OX40L/OX40 signaling promotes pathogenic T-cell proliferation in multiple pathways (Th2, Th1, Th17, Th22) in atopic dermatitis; contributes to chronic T-cell inflammation
PMID: 38836560
4
TNFSF4 is a genome-wide significant risk locus for IgA nephropathy; part of inflammatory signaling pathway convergence prioritizing drug targets
PMID: 37337107
5
TNFSF4-TNFRSF4 interactions increased in thyroid-associated ophthalmopathy based on cell-cell communication analysis
PMID: 35896115
6
TNFSF4-TNFRSF4 interaction pair identified as potential therapeutic target in esophageal squamous cell carcinoma immunotherapy
PMID: 38566201
7
OX40L promotes T-cell activation and differentiation; AD patients show higher OX40 expression on PBMCs than healthy controls
PMID: 38607026
Disease Associationsⓘ21
systemic lupus erythematosusOpen Targets
0.59Moderate
asthmaOpen Targets
0.58Moderate
atopic eczemaOpen Targets
0.54Moderate
allergic rhinitisOpen Targets
0.50Moderate
Eczematoid dermatitisOpen Targets
0.49Moderate
rheumatoid arthritisOpen Targets
0.48Moderate
childhood onset asthmaOpen Targets
0.45Moderate
respiratory system diseaseOpen Targets
0.44Moderate
allergic diseaseOpen Targets
0.43Moderate
deep vein thrombosisOpen Targets
0.42Moderate
Crohn's diseaseOpen Targets
0.38Weak
Abnormal thrombosisOpen Targets
0.35Weak
rhinitisOpen Targets
0.34Weak
systemic sclerodermaOpen Targets
0.33Weak
atopic asthmaOpen Targets
0.32Weak
allergic conjunctivitisOpen Targets
0.32Weak
autoimmune disorder of musculoskeletal systemOpen Targets
0.30Weak
narcolepsy-cataplexy syndromeOpen Targets
0.29Weak
chondrocalcinosisOpen Targets
0.28Weak
dermatitisOpen Targets
0.26Weak
Systemic lupus erythematosusUniProt
Pathogenic Variants
No pathogenic variants reported on ClinVar for this gene.
View on ClinVar ↗
Drug Targets2
AMLITELIMABPhase III
Tumor necrosis factor ligand superfamily member 4 inhibitor
atopic eczema
OXELUMABPhase II
Tumor necrosis factor ligand superfamily member 4 inhibitor
asthma
Related Genes
IL10Protein interaction98%TNFProtein interaction97%IL6Protein interaction97%CD80Protein interaction96%CTLA4Protein interaction96%PDCD1LG2Protein interaction95%
Tissue Expression6 tissues
Lung
100%
Brain
84%
Ovary
69%
Liver
66%
Heart
56%
Bone Marrow
42%
Gene Interaction Network
Click a node to explore
TNFSF4IL10TNFIL6CD80CTLA4PDCD1LG2
PROTEIN STRUCTURE
Preparing viewer…
PDB2HEV · 2.41 Å · X-ray
View on RCSB ↗
Constraintⓘ
LOEUFⓘ
0.99LoF Tolerant
pLIⓘ
0.59Intermediate
Observed/Expected LoF0.21 [0.07–0.99]
RankingsWhere TNFSF4 stands among ~20K protein-coding genes
  • #2,678of 20,598
    Most Researched167 · top quartile
  • #9,497of 17,882
    Most Constrained (LOEUF)0.99
Genes detectedTNFSF4
Sources retrieved26 papers
Response time—
📄 Sources
26▼
1
OX40, OX40L and Autoimmunity: a Comprehensive Review.
PMID: 26215166
Clin Rev Allergy Immunol · 2016
1.00
2
Single-cell profiling of response to neoadjuvant chemo-immunotherapy in surgically resectable esophageal squamous cell carcinoma.
PMID: 38566201
Genome Med · 2024
0.90
3
The role of OX40 ligand/OX40 axis signalling in atopic dermatitis.
PMID: 38836560
Br J Dermatol · 2024
0.80
4
Single-cell RNA sequencing depicts the local cell landscape in thyroid-associated ophthalmopathy.
PMID: 35896115
Cell Rep Med · 2022
0.70
5
Association of EBF1, FAM167A(C8orf13)-BLK and TNFSF4 gene variants with primary Sjögren's syndrome.
PMID: 20861858
Genes Immun · 2011
0.64