Tumor necrosis factor receptor superfamily member 4 (OX40) and Tumor necrosis factor ligand superfamily member 4 (OX40L) complex (OX40/OX40L)

The OX40/OX40L complex is a pivotal co-stimulatory signaling unit within the immune system, comprising the Tumor necrosis factor receptor superfamily member 4 (OX40, CD134) and its ligand, Tumor necrosis factor ligand superfamily member 4 (OX40L, CD252). OX40 is primarily expressed on activated CD4+ and CD8+ T cells, whereas OX40L is expressed on professional antigen-presenting cells like dendritic cells, B cells, and vascular endothelial cells (UniProt P43489, P23510). Binding of OX40L to OX40 triggers downstream signaling pathways, such as NF-κB and PI3K/Akt, which enhance T-cell proliferation, cytokine production, and long-term survival (PubMed: 24591374). This pathway plays a dual role in clinical development: agonists are utilized in oncology to bolster anti-tumor T-cell responses, while antagonists are employed in autoimmune and inflammatory diseases to inhibit the activity of self-reactive T cells (PubMed: 30305315). Current therapeutic candidates include monoclonal antibodies like rocatinlimab and amlitelimab, which target this axis to treat conditions such as atopic dermatitis by depleting or inhibiting pathogenic T cells (PubMed: 34919948). The complex is also a target in graft-versus-host disease and asthma research due to its role in maintaining the balance between effector and regulatory T-cell populations. Overall, the OX40/OX40L interaction serves as a critical checkpoint for modulating the intensity and duration of adaptive immune responses.

Other names

CD134/CD252 complexTNFRSF4/TNFSF4 complexOX40/OX40L axisACT35/TXGP1 complexOX40 receptor/OX40 ligand complex

Agonism of the OX40 receptor to enhance T-cell effector function and survival for cancer immunotherapy, or antagonism of the OX40/OX40L interaction to suppress pathogenic T-cell responses in autoimmune and inflammatory diseases.