TNF Superfamily Pathway: Human Ligand-Receptor Interactions & their Associated Functions

Click on the boxes below to see the TNF superfamily ligands and receptors that are involved in regulating these processes.

4-1BB Ligand
4-1BB Ligand
APRIL
APRIL
BAFF
BAFF
CD27 Ligand
CD27 Ligand
CD30 Ligand
CD30 Ligand
CD40 Ligand
CD40 Ligand
EDA-A1
EDA-A1
EDA-A2
EDA-A2
TRAIL
TRAIL
TRANCE/RANK Ligand
TRANCE/RANK Ligand
Unknown Ligand
Unknown Ligand
Fas Ligand
Fas Ligand
GITR Ligand
GITR Ligand
LIGHT
LIGHT
TL1A/VEGI
TL1A/VEGI
TWEAK
TWEAK
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TNF-alpha
TNF-alpha
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TNF-beta/
Lymphotoxin
alpha
TNF-beta/
Lymphotoxin
alpha
Lymphotoxin
alpha1/beta2
Lymphotoxin
alpha1/beta2
Lymphotoxin
alpha2/beta1
Lymphotoxin
alpha2/beta1
OX40 Ligand
OX40 Ligand
Neurotrophins
Neurotrophins
APP
APP
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Unknown Ligand
Unknown Ligand
4-1BB
4-1BB
BCMA
BCMA
TACI
TACI
BAFF R
BAFF R
CD27
CD27
CD30
CD30
CD40
CD40
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EDAR
EDAR
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XEDAR
XEDAR
TRAIL R1
TRAIL R1
TRAIL R2
TRAIL R2
TRAIL R3
TRAIL R3
TRAIL R4
TRAIL R4
OPG
OPG
RANK
RANK
TROY
TROY
Fas
Fas
GITR
GITR
DcR3
DcR3
HVEM
HVEM
DR3
DR3
TWEAK R
TWEAK R
TNF RI
TNF RI
TNF RII
TNF RII
Lymphotoxin beta R
Lymphotoxin beta R
OX40
OX40
NGF R
NGF R
DR6
DR6
RELT
RELT

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.

To learn more, please visit our TNF Superfamily Research Area.