TNFR2

TNFR2, also known as tumor necrosis factor receptor 2 or CD120b, is a cell-surface receptor of the TNF receptor superfamily encoded by the TNFRSF1B gene. It is a type I transmembrane protein expressed in a limited set of cell types, notably regulatory T cells, certain activated T cells, endothelial cells, and some myeloid and neural cells. It binds tumor necrosis factor (TNF) with a preference for membrane-bound TNF-α, though lymphotoxin-α can also engage it.

Structure and signaling: TNFR2 lacks the death domain found in TNFR1 and signals primarily through adaptor proteins such as TRAF2, TRAF1, and cellular inhibitors of apoptosis (cIAPs). Ligand binding activates NF-κB and MAPK pathways and can trigger PI3K–Akt signaling, promoting cell survival, proliferation, and cytokine production. A notable function is promoting expansion and suppressive activity of regulatory T cells (Tregs), contributing to immune regulation and tissue homeostasis. TNFR2 can also participate in reverse signaling when engaged on ligand-bearing cells.

Regulation and soluble receptor: TNFR2 activity is modulated by the presence of its soluble form, sTNFR2, generated by ectodomain shedding; sTNFR2 can bind TNF and limit its availability. Expression of TNFR2 is upregulated in inflammatory contexts and in the tumor microenvironment where Tregs are enriched, influencing disease outcomes.

Clinical and therapeutic relevance: Because of its role in Treg biology and immune regulation, TNFR2 is studied as a therapeutic target. Agonists of TNFR2 are explored to enhance Treg function in autoimmune conditions, while antagonists or blocking strategies are investigated to reduce immunosuppression in cancer. Ongoing research seeks to clarify context-dependent effects across tissues and diseases.