Death Receptor 3

Death receptor 3 (DR3, TNFRSF25, also LARD or Apo-3) is a TNF receptor superfamily protein that shares highest homology with TNFR1 but is distinguished by its restricted expression and ligand specificity. DR3 transcripts are found mainly on T lymphocytes-at low levels in naive and memory T cells and markedly induced during T-cell activation-as well as in intestinal epithelial cells and NK cells. Its sole known ligand is TL1A (TNFSF15). Upon TL1A engagement, DR3 recruits TRADD, TRAF2, RIPK1 and caspase-8, coupling to NF-κB activation and survival in most contexts, but to apoptosis when caspase activity is compromised. Functionally, DR3 acts as a co-stimulator selectively boosting Th1, Th2, Th9 and Th17 responses and expanding tissue-resident memory T cells, which enhances protective immunity but concurrently amplifies autoimmune inflammation. TL1A-DR3 signaling is strongly implicated in inflammatory bowel disease, rheumatoid arthritis, psoriasis, asthma and multiple sclerosis; genetic deletion of DR3 protects mice from experimental colitis and EAE.