Overview of the TNF Superfamily Ligands & Receptors
Tumor Necrosis Factor (TNF) was initially described and named for its tumor regression activity, although its identity was unknown. The first TNF superfamily members to be identified were TNF-alpha and TNF-beta/Lymphotoxin alpha (LT-alpha), which were purified and identified as two related proteins fitting the TNF description. To date, 19 TNF superfamily ligands have been identified along with 32 TNF superfamily receptors.
Most TNF superfamily ligands are type II transmembrane proteins whose extracellular domains can be cleaved by specific metalloproteinases to generate soluble cytokines. Cleaved and non-cleaved ligands are active as non-covalent homotrimers or heterotrimers. TNF superfamily ligands are characterized by a stalk of varying length connecting the transmembrane domain to the core region, which contains the hallmark structure of TNF superfamily ligands, the TNF homology domain (THD). Receptors for these proteins are oligomeric, type I or type III transmembrane proteins that contain multiple extracellular cysteine-rich domains. Several of these receptors also contain intracellular death domains (DDs) that recruit caspase-interacting proteins following ligand binding to initiate the extrinsic pathway of caspase activation. Other TNF superfamily receptors that lack death domains bind TNF receptor-associated factors (TRAFs) and activate intracellular signaling pathways that can lead to proliferation or differentiation. These DD-lacking TNF superfamily receptors can also initiate apoptosis, but they do so via indirect mechanisms.
While many TNF superfamily members promote or inhibit apoptosis, they also regulate critical functions of both the innate and adaptive immune system including natural killer cell activation, T cell co-stimulation, and B cell homeostasis and activation. In addition, several TNF superfamily members regulate cell type-specific responses such as hair follicle and osteoclast development