Death receptor 3

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Death receptor 3 (DR3), also known as tumor necrosis factor receptor superfamily member 25 (TNFRSF25), is a cell surface receptor of the tumor necrosis factor receptor superfamily which mediates apoptotic signalling and differentiation.[1][2][3] Its only known TNFSF ligand is TNF-like protein 1A (TL1A).[4]


The protein encoded by this gene is a member of the TNF-receptor superfamily. This receptor is expressed preferentially by activated and antigen-experienced T lymphocytes. TNFRSF25 is also highly expressed by FoxP3 positive regulatory T lymphocytes. TNFRSF25 is activated by a monogamous ligand, known as TL1A (TNFSF15), which is rapidly upregulated in antigen presenting cells and some endothelial cells following Toll-Like Receptor or Fc receptor activation. This receptor has been shown to signal both through the TRADD adaptor molecule to stimulate NF-kappa B activity or through the FADD adaptor molecule to stimulate caspase activation and regulate cell apoptosis.[2]

Multiple alternatively spliced transcript variants of this gene encoding distinct isoforms have been reported, most of which are potentially secreted molecules. The alternative splicing of this gene in B and T cells encounters a programmed change upon T-cell activation, which predominantly produces full-length, membrane bound isoforms, and is thought to be involved in controlling lymphocyte proliferation induced by T-cell activation. Specifically, activation of TNFRSF25 is dependent upon previous engagement of the T cell receptor. Following binding to TL1A, TNFRSF25 signaling increases the sensitivity of T cells to endogenous IL-2 via the IL-2 receptor and enhances T cell proliferation. Because the activation of the receptor is T cell receptor dependent, the activity of TNFRSF25 in vivo is specific to those T cells that are encountering cognate antigen. At rest, and for individuals without underlying autoimmunity, the majority of T cells that regularly encounter cognate antigen are FoxP3+ regulatory T cells. Stimulation of TNFRSF25, in the absence of any other exogenous signals, stimulates profound and highly specific proliferation of FoxP3+ regulatory T cells from their 8-10% of all CD4+ T cells to 35-40% of all CD4+ T cells within 5 days.[5]


Therapeutic agonists of TNFRSF25 can be used to stimulate Treg expansion, which can reduce inflammation in experimental models of asthma, allogeneic solid organ transplantation and ocular keratitis.[5][6][7] Similarly, because TNFRSF25 activation is antigen dependent, costimulation of TNFRSF25 together with an autoantigen or with a vaccine antigen can lead to exacerbation of immunopathology or enhanced vaccine-stimulated immunity, respectively.[8] TNFRSF25 stimulation is therefore highly specific to T cell mediated immunity, which can be used to enhance or dampen inflammation depending on the temporal context and quality of foreign vs self antigen availability. Stimulation of TNFRSF25 in humans may lead to similar, but more controllable, effects as costimulatory blockade targeting molecules such as CTLA-4 and PD-1.[3]


  1. Bodmer JL, Burns K, Schneider P, Hofmann K, Steiner V, Thome M, Bornand T, Hahne M, Schröter M, Becker K, Wilson A, French LE, Browning JL, MacDonald HR, Tschopp J (Jan 1997). "TRAMP, a novel apoptosis-mediating receptor with sequence homology to tumor necrosis factor receptor 1 and Fas(Apo-1/CD95)". Immunity. 6 (1): 79–88. doi:10.1016/S1074-7613(00)80244-7. PMID 9052839.
  2. 2.0 2.1 Kitson J, Raven T, Jiang YP, Goeddel DV, Giles KM, Pun KT, Grinham CJ, Brown R, Farrow SN (Nov 1996). "A death-domain-containing receptor that mediates apoptosis". Nature. 384 (6607): 372–5. doi:10.1038/384372a0. PMID 8934525.
  3. 3.0 3.1 "Entrez Gene: TNFRSF25 tumor necrosis factor receptor superfamily, member 25".
  4. Wang EC (Sep 2012). "On death receptor 3 and its ligands…". Immunology. 137 (1): 114–6. doi:10.1111/j.1365-2567.2012.03606.x. PMC 3449252. PMID 22612445.
  5. 5.0 5.1 Schreiber TH, Wolf D, Tsai MS, Chirinos J, Deyev VV, Gonzalez L, Malek TR, Levy RB, Podack ER (Oct 2010). "Therapeutic Treg expansion in mice by TNFRSF25 prevents allergic lung inflammation". The Journal of Clinical Investigation. 120 (10): 3629–40. doi:10.1172/JCI42933. PMC 2947231. PMID 20890040.
  6. J Reddy PB, Schreiber TH, Rajasagi NK, Suryawanshi A, Mulik S, Veiga-Parga T, Niki T, Hirashima M, Podack ER, Rouse BT (Oct 2012). "TNFRSF25 agonistic antibody and galectin-9 combination therapy controls herpes simplex virus-induced immunoinflammatory lesions". Journal of Virology. 86 (19): 10606–20. doi:10.1128/JVI.01391-12. PMC 3457251. PMID 22811539.
  7. Wolf D, Schreiber TH, Tryphonopoulos P, Li S, Tzakis AG, Ruiz P, Podack ER (Sep 2012). "Tregs expanded in vivo by TNFRSF25 agonists promote cardiac allograft survival". Transplantation. 94 (6): 569–74. doi:10.1097/TP.0b013e318264d3ef. PMID 22902792.
  8. Schreiber TH, Wolf D, Bodero M, Gonzalez L, Podack ER (Oct 2012). "T cell costimulation by TNFR superfamily (TNFRSF)4 and TNFRSF25 in the context of vaccination". Journal of Immunology. 189 (7): 3311–8. doi:10.4049/jimmunol.1200597. PMC 3449097. PMID 22956587.

Further reading

This article incorporates text from the United States National Library of Medicine, which is in the public domain.