The tumor necrosis factor (TNF) ligand and receptor superfamilies play an important role in cell proliferation, survival, and death. Stimulating or inhibiting TNF superfamily signaling pathways is expected to have therapeutic benefit for patients with various diseases, including cancer, autoimmunity, and infectious diseases. We review our current understanding of the structure and geometry of TNF superfamily ligands, receptors, and their interactions. A trimeric ligand and three receptors, each binding at the interface of two ligand monomers, form the basic unit of signaling. Clustering of multiple receptor subunits is necessary for efficient signaling. Current reports suggest that the receptors are prearranged on the cell surface in a “nonsignaling,” resting state in a large hexagonal structure of antiparallel dimers. Receptor activation requires ligand binding, and cross-linking antibodies can stabilize the receptors, thereby maintaining the active, signaling state. On the other hand, an antagonist antibody that locks receptor arrangement in antiparallel dimers effectively blocks signaling. This model may aid the design of more effective TNF signaling–targeted therapies.

肿瘤坏死因子（TNF）配体和受体超家族在细胞增殖，存活和死亡中起重要作用。预期刺激或抑制TNF超家族信号传导途径对患有多种疾病，包括癌症，自身免疫和感染性疾病的患者具有治疗益处。我们回顾了我们目前对TNF超家族配体，受体及其相互作用的结构和几何学的理解。三聚体配体和三个受体，每个在两个配体单体的界面处结合，形成信号传导的基本单元。多个受体亚基的聚集对于有效的信号传递是必需的。当前的报道表明，受体以“无信号”的静止状态预先排列在细胞表面，处于反平行二聚体的大六边形结构中。受体活化需要配体结合，并且交联抗体可以稳定受体，从而保持活跃的信号状态。另一方面，将受体排列锁定在反平行二聚体中的拮抗剂抗体可有效阻断信号传导。该模型可能有助于设计更有效的针对TNF信号的疗法。