TNF Superfamily Ligands and Receptors

TNF Superfamily Ligand-Receptor Interactions & Select Functions

TNF Superfamily Proteins

The tumor necrosis factor superfamily (TNFSF) in humans consists of 19 proteins that play important roles in regulating the proliferation, differentiation, activation, and survival of multiple immune and non-immune cell types. Some TNF superfamily proteins transduce signals that lead to apoptosis, while others are involved in regulating innate and adaptive immune responses, and still others promote cell-type specific responses such as osteoclast development. TNF-alpha was the first TNF superfamily protein to be identified, followed by Lymphotoxin-alpha (LT-alpha)/TNF-beta, which was found to bind to the same receptor as TNF-alpha and share 50% amino acid sequence homology. Seventeen other related proteins were subsequently identified based on their sequence homologies with TNF-alpha. With the exception of Lymphotoxin-alpha (LT-alpha)/TNF-beta, all members of the TNF superfamily are type II transmembrane proteins that share a common structural motif known as the TNF homology domain (THD), which mediates both their trimerization and receptor-binding capabilities. While most TNF superfamily proteins are synthesized as membrane-bound proteins, cleavage of their extracellular domains by specific metalloproteinases gives rise to soluble forms of the proteins. TNF superfamily proteins are primarily expressed by antigen-presenting cells, such as dendritic cells, macrophages, B cells, and neutrophils, but they can also be expressed by T cells, natural killer cells, basophils, eosinophils, mast cells, endothelial cells, and thymic epithelial cells.

TNF Receptor Superfamily

Members of the TNF superfamily bind to receptors belonging to the TNF receptor superfamily (TNFRSF), which consists of 29 receptors in humans and 32 in mice. With the exception of BAFF R, BCMA, TACI, and XEDAR, which are type III transmembrane proteins, TNF superfamily receptors are type I transmembrane proteins or soluble decoy receptors. The extracellular domains of all TNF receptors are characterized by the presence of one or more highly conserved, cysteine-rich domain(s) that mediates ligand binding. High affinity binding of a TNFSF trimer to its receptor promotes receptor clustering and trimerization, leading to formation of a 3:3 hexameric ligand-receptor complex and activation of downstream signaling pathways. As is outlined in the graphic above, several TNF superfamily ligands can bind to more than one receptor, which creates a complex network of interactions that can mediate immune responses and inflammation.

TNF Signaling Pathways

TNF superfamily receptors can be separated into three groups: 1) those that contain cytoplasmic death domains (DD) and promote caspase activation and apoptosis; 2) those that lack an intracellular death domain and associate with members of the TNF receptor-associated factor (TRAF) family of E3 ubiquitin ligases to activate NF-kappa B and MAPK signaling pathways that regulate inflammation, and cell survival or death; and 3) those that lack a cytoplasmic domain and function as decoy receptors.

TNF Superfamily Death Receptors

Death domain-containing TNF superfamily receptors are involved in initiating the extrinsic pathway of caspase activation and apoptosis. These receptors include Fas/CD95, DR3, TNF RI, TRAIL R1, TRAIL R2, EDAR, NGF R, and DR6. Activation of most of these receptors promotes their interaction with death domain-containing intracellular adaptor proteins, such as the Fas-associated death domain (FADD) and TNFR-associated death domain (TRADD) proteins, which subsequently recruit Caspase-8 and Caspase-10, resulting in apoptotic signaling. In addition to these pathways, activation of death domain-containing TNF superfamily receptors can also trigger p38, JNK, and NF-kappa B signaling to promote cell survival, the production of pro-inflammatory cytokines and chemokines, and innate and adaptive immune responses.

TRAF-Associated TNF Superfamily Receptors

Other TNF superfamily receptors interact with TRAF (TRAF-1-7) adaptor proteins to regulate intracellular signaling. Signaling pathways activated downstream of the TRAF-associated TNF superfamily receptors include the canonical and non-canonical NF-kappa B pathways, the PI 3-kinase/Akt pathway, and the JNK, p38, and ERK MAPK signaling pathways. These pathways promote proliferation, differentiation, and survival in a cell type-specific and context-dependent manner. Through these pathways, TNF superfamily proteins regulate the activities of multiple immune cell types, including T cell co-stimulation, natural killer cell activation, B cell homeostasis and activation, and dendritic cell homeostasis and licensing, as well as cell type-specific responses such as hair follicle formation and osteoclast differentiation. TNF superfamily receptors belonging to the TRAF-associated group include 4-1BB, BAFF R, BCMA, CD27, CD30, CD40, GITR, HVEM, LT-beta R, OX40, RANK, TACI, TNF RII, TWEAK R, and XEDAR.

TNF Superfamily Decoy Receptors

The final group of TNF superfamily receptors is the decoy receptors, which lack cytoplasmic domains and as a result, are incapable of initiating intracellular signaling. Members of this group include DcR3, TRAIL R3, TRAIL R4, and OPG. These receptors compete with signaling receptors for ligand binding, and thus, have the ability to inhibit the effects of signaling receptors.

TNF Superfamily and Disease

Due to the abilities of TNFSF/TNFRSF interactions to regulate immune cell activities, inflammation, and apoptosis, many TNF superfamily proteins have been implicated in the pathogenesis of chronic inflammatory diseases, autoimmune disorders, osteoporosis, rheumatoid arthritis, and cancer. Consequently, inhibitors of many TNF superfamily proteins or their receptors are being investigated as potential therapeutics for treating these different diseases. Additionally, since a number of TNF superfamily proteins have been shown to stimulate T cell or natural killer cell survival, proliferation, and effector functions, agonists of T and NK cell stimulatory TNFSF receptors are also being explored as potential therapies for treating cancer.

Bio-Techne offers a wide selection of high quality reagents to facilitate the study of TNF superfamily members including R&D Systems™ bioactive recombinant proteins, single and multianalyte immunoassays in a number of different formats, and antibodies for blocking/neutralization, immunohistochemistry, immunoprecipitation, Western blotting, and flow cytometry.