TNFRSF4

Official Full Name

TNF receptor superfamily member 4

Organism

Homo sapiens

GeneID

7293

Background

The protein encoded by this gene is a member of the TNF-receptor superfamily. This receptor has been shown to activate NF-kappaB through its interaction with adaptor proteins TRAF2 and TRAF5. Knockout studies in mice suggested that this receptor promotes the expression of apoptosis inhibitors BCL2 and BCL2lL1/BCL2-XL, and thus suppresses apoptosis. The knockout studies also suggested the roles of this receptor in CD4+ T cell response, as well as in T cell-dependent B cell proliferation and differentiation. [provided by RefSeq, Jul 2008]

Synonyms

OX40; ACT35; CD134; IMD16; TXGP1L;

Protein Sequence

MCVGARRLGRGPCAALLLLGLGLSTVTGLHCVGDTYPSNDRCCHECRPGNGMVSRCSRSQNTVCRPCGPGFYNDVVSSKPCKPCTWCNLRSGSERKQLCTATQDTVCRCRAGTQPLDSYKPGVDCAPCPPGHFSPGDNQACKPWTNCTLAGKHTLQPASNSSDAICEDRDPPATQPQETQGPPARPITVQPTEAWPRTSQGPSTRPVEVPGGRAVAAILGLGLVLGLLGPLAILLALYLLRRDQRLPPDAHKPPGGGSFRTPIQEEQADAHSTLAKI

Open

Disease

Atopic eczema, Metastatic malignant neoplasm, Prostate cancer, Solid tumour/cancer

Approved Drug

Clinical Trial Drug

11 +

Discontinued Drug

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Detailed Information

TNFRSF4, also known as OX40 or CD134, is located on human chromosome 1p36.33 and consists of seven exons encoding a 277-amino-acid type I transmembrane protein. As a member of the tumor necrosis factor receptor (TNFR) superfamily, its extracellular region contains three characteristic cysteine-rich domains (CRDs) responsible for specific binding to its ligand, TNFSF4 (OX40L). The intracellular domain lacks intrinsic enzymatic activity but contains a conserved TRAF-binding motif, particularly the C-terminal QEE sequence, which recruits TRAF2, TRAF3, and TRAF5. This structural feature underpins the core mechanism of OX40-mediated signal transduction.

Figure 1. Schematic diagram of the two-step OX40L costimulation model. (Fu Y, et al., 2020)

OX40-OX40L interaction induces receptor trimerization, conformational changes, and recruitment of TRAF adaptor proteins. The resulting signaling complex activates two key pathways: (i) the canonical NF-κB pathway, where the IKK complex phosphorylates and degrades IκBα, allowing p50-RelA dimers to translocate to the nucleus and initiate transcription of survival genes such as BCL2 and BCL2L1; (ii) the PI3K-Akt-mTOR pathway, which enhances glucose metabolism and protein synthesis through phosphorylation cascades, synergistically promoting T cell proliferation and survival. OX40 signaling also induces anti-apoptotic protein c-FLIP expression, inhibiting caspase-8 activation and antagonizing death receptor-mediated apoptosis.

Physiological and Pathological Functions

In physiological immune responses, TNFRSF4 is predominantly expressed on activated CD4⁺ and CD8⁺ T cells, but not on naïve T cells. Its ligand, OX40L, is highly expressed on activated antigen-presenting cells such as dendritic cells and B cells. OX40-OX40L interaction provides a critical co-stimulatory signal within 24–72 hours post-T cell activation, later than CD28-CTLA4 signaling. Key functions include:

Promoting effector T cell expansion and survival, prolonging the immune response duration.
Suppressing activation-induced cell death (AICD), maintaining effector T cell pools.
Reducing Treg-mediated immunosuppression, relieving immune tolerance.
Driving memory T cell differentiation to enhance secondary responses.

Pathologically, TNFRSF4 signaling exhibits a "dual nature." In anti-tumor immunity, OX40 enhances cytotoxic CD8⁺ T cell activity and promotes secretion of effector cytokines such as IFN-γ and TNF-α. Conversely, in autoimmune diseases such as rheumatoid arthritis and multiple sclerosis, overactivation leads to pathogenic T cell infiltration and chronic inflammation. Bioinformatics studies in NSCLC indicate that low TNFSF4 (OX40L) expression correlates with resistance to bevacizumab plus pemetrexed therapy, impairing OX40-mediated T cell activation and immune surveillance.

Certain viral pathogens exploit TNFRSF4 for immune evasion. Human herpesvirus 6B (HHV-6B) uses OX40 as a cellular entry receptor, with viral U21 protein binding the extracellular domain to mediate viral internalization and suppress T cell function, particularly in post-transplant HHV-6B reactivation.

Challenges and Future Directions

Despite promising results, TNFRSF4-targeted therapies face several challenges:

Dose-dependent effects: Low-dose OX40 agonists enhance T cell proliferation, whereas high doses may induce apoptosis, as seen in MEDI0562 Phase I trials.
Spatiotemporal regulation: OX40 signaling boosts effector T cell function early in the immune response, but prolonged activation in chronic infections or tumors may cause T cell exhaustion. Optimized dosing schedules (e.g., sequential use with vaccines) may improve efficacy.
Biomarker limitations: Reliable predictive biomarkers are lacking. Preliminary evidence suggests pre-treatment tumor OX40⁺ T cell infiltration correlates with response to MEDI6383 (OX40L trimer agonist), requiring validation in larger cohorts.

Future directions include developing conditionally activated antibodies (e.g., PROTAC-OX40) specific to the tumor microenvironment, designing bispecific molecules (OX40xPD-L1) for simultaneous checkpoint inhibition and co-stimulation, and combining with metabolic modulators such as IDO inhibitors to reverse immunosuppressive microenvironments.

Reference

Webb GJ, Hirschfield GM, Lane PJ. OX40, OX40L and Autoimmunity: a Comprehensive Review. Clin Rev Allergy Immunol. 2016 Jun;50(3):312-32.
Fu Y, Lin Q, Zhang Z, Zhang L. Therapeutic strategies for the costimulatory molecule OX40 in T-cell-mediated immunity. Acta Pharm Sin B. 2020 Mar;10(3):414-433.

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