TNFRSF25. also known as death receptor 3 (DR3), is a member of the tumor necrosis factor receptor superfamily (TNFRSF) and plays a critical role in regulating immune responses. It is primarily expressed on activated T cells, natural killer T (NKT) cells, and innate lymphoid cells. Its ligand, TL1A (TNFSF15), binds to TNFRSF25 to activate downstream signaling pathways, including NF-κB and MAPK, which modulate inflammatory processes, T-cell proliferation, and cytokine production. TNFRSF25 is implicated in autoimmune diseases, such as rheumatoid arthritis and inflammatory bowel disease, where its overactivation contributes to chronic inflammation.
Antibodies targeting TNFRSF25 are designed to either block or agonize its signaling for therapeutic purposes. Blocking antibodies inhibit the TNFRSF25-TL1A interaction, reducing pro-inflammatory cytokine release and immune cell activation, making them potential treatments for autoimmune disorders. Conversely, agonist antibodies can enhance TNFRSF25 signaling to promote regulatory T-cell (Treg) expansion or apoptosis of pathogenic T cells, which may benefit conditions like cancer or transplantation tolerance. Research also explores TNFRSF25 antibodies as diagnostic tools to quantify receptor expression in diseased tissues.
Despite promising preclinical data, clinical translation remains challenging due to the receptor's dual roles in pro- and anti-inflammatory pathways. Ongoing studies aim to clarify context-dependent mechanisms and optimize antibody specificity to minimize off-target effects. These efforts highlight TNFRSF25 as a versatile therapeutic target in immunomodulation.