Affinage

TNFRSF25

Tumor necrosis factor receptor superfamily member 25 · UniProt Q93038

Length
417 aa
Mass
45.4 kDa
Annotated
2026-06-10
100 papers in source corpus 27 papers cited in narrative 27 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/8 claims corpus-supported (88%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TNFRSF25 (DR3) is a death domain-containing TNF receptor superfamily member that couples ligand engagement to a binary cell-fate decision between apoptosis and survival/proliferation (PMID:8875942). Upon binding its cognate ligand TL1A (TNFSF15), DR3 nucleates an intracellular signaling complex of TRADD, TRAF2, and RIP that drives NF-κB together with ERK, JNK, and p38 MAPK activation (PMID:11911831, PMID:12882979), while in apoptosis-competent settings FADD and caspase-8 are recruited to execute death; caspase-8 is the non-redundant effector of DR3-induced killing, since its loss abolishes apoptosis while leaving JNK and IκBα-dependent NF-κB signaling intact (PMID:9729047). The death-versus-survival balance is set by NF-κB-induced c-IAP2, which restrains apoptosis (PMID:12882979), and by an activation-coupled alternative-splicing switch that selects the full-length transmembrane receptor required for TL1A responsiveness (PMID:9114039, PMID:16698931). Beyond molecular wiring, DR3 is a critical costimulatory receptor in adaptive and innate immunity: it mediates thymocyte negative selection (PMID:11313471) and, downstream of dendritic-cell-derived TL1A, promotes effector T cell accumulation and cytokine production at inflammatory sites across Th1, Th2, Th9, Th17, and CD8+ CTL responses without controlling lineage priming or polarization (PMID:18571443, PMID:18411341, PMID:18411337, PMID:21688261, PMID:25786692). Agonistic DR3 signaling selectively expands Foxp3+ Tregs through TCR/MHC II-, IL-2R-, and Akt-dependent signaling (PMID:20890040, PMID:24242819), an activity partly dependent on the DR3-binding lectin Galectin-9 (PMID:28877989). In innate and stromal compartments DR3 drives ILC3 GM-CSF production via p38 MAPK (PMID:31358760), activates adipose ILC2s through NF-κB (PMID:32948777), promotes osteoclastogenesis with CCL3/MMP-9 output (PMID:28062298), and signals directly on fibroblasts through Rho-pathway activation to drive intestinal fibrosis (PMID:33097818). DR3 specifically does not serve as the functional receptor for TWEAK (PMID:11094155). DR3 promoter hypermethylation silencing its expression is linked to rheumatoid arthritis synovial cells (PMID:16508942).

Mechanistic history

Synthesis pass · year-by-year structured walk · 22 steps
  1. 1996 High

    Established DR3 as a death-domain TNF receptor that bifurcates into apoptosis and NF-κB outputs, defining the core signaling problem.

    Evidence Molecular cloning with overexpression, Co-IP of the TRADD/TRAF2/FADD/caspase-8 complex, and functional apoptosis/NF-κB assays

    PMID:8875942

    Open questions at the time
    • Endogenous ligand unidentified at this stage
    • Physiological cell type and context of signaling unknown
  2. 1997 High

    Showed that alternative splicing generates multiple isoforms and that an activation-coupled switch selects the membrane-bound apoptosis-competent form, linking receptor availability to lymphocyte state.

    Evidence cDNA cloning/sequencing of isoforms, overexpression apoptosis readout in 293T, RT-PCR of splice forms before/after T cell activation

    PMID:9114039

    Open questions at the time
    • Function of secreted isoforms unresolved
    • Splicing regulators not identified
  3. 1998 High

    Genetically separated death from survival signaling by showing caspase-8 is required for DR3-induced apoptosis but dispensable for JNK and NF-κB activation.

    Evidence Casp8-knockout fibroblasts with apoptosis, JNK, and IκBα degradation assays

    PMID:9729047

    Open questions at the time
    • Order of complex assembly not resolved
    • Determinants selecting death vs. survival in vivo unknown
  4. 2000 Medium

    Excluded TWEAK as a DR3 ligand, narrowing the search for the cognate ligand.

    Evidence In vitro binding assays and DR3-knockout cell responsiveness tests

    PMID:11094155

    Open questions at the time
    • Negative result; did not identify the true ligand
  5. 2002 High

    Identified TL1A (TNFSF15) as the DR3 ligand and a decoy receptor TR6/DcR3, connecting an endothelial cytokine to DR3-driven apoptosis, NF-κB, and T cell costimulation.

    Evidence Ligand-receptor binding, NF-κB reporter and apoptosis assays in DR3+ lines, T cell cytokine assays, TR6-Fc antagonism in vitro and in vivo

    PMID:11911831

    Open questions at the time
    • In vivo cellular source of TL1A not defined here
    • Mechanism balancing apoptosis vs. costimulation unresolved
  6. 2003 High

    Defined the TL1A-induced DR3 complex (TRADD/TRAF2/RIP) and showed NF-κB-induced c-IAP2 gates apoptosis, explaining context-dependent cell fate.

    Evidence Reciprocal Co-IP, NF-κB reporter, MAPK kinase assays, c-IAP2 RNAi rescue in TF-1 cells

    PMID:12882979

    Open questions at the time
    • FADD/caspase-8 recruitment context-dependent and cell-type-specific
    • Quantitative threshold of c-IAP2 control unknown
  7. 2005 Medium

    Distinguished DR3 from TNFR1 by mapping a unique TAK1/ASK1–MKK4/MKK7–JNK2 axis for IL-8 induction despite shared TRAF2/NF-κB use.

    Evidence Overexpression in HEK293 with dominant-negative kinase constructs and IL-8 reporter assays

    PMID:16324699

    Open questions at the time
    • Single cell model and overexpression-based
    • Endogenous relevance of the kinase axis untested
  8. 2005 Low

    Proposed a four-CRD architecture and modeled how an RA-linked D158G mutation might destabilize ligand binding.

    Evidence Comparative homology modeling and energy minimization (no experimental structure)

    PMID:15694416

    Open questions at the time
    • Computational only; no structural or mutagenesis validation
    • Predicted destabilization not experimentally confirmed
  9. 2006 Medium

    Confirmed in vivo that activation upregulates the full transmembrane DR3 form mediating TL1A costimulation of memory CD4+ T cells and IFN-γ.

    Evidence RT-PCR isoform analysis in intestinal inflammation models plus TL1A stimulation and cytokine ELISA

    PMID:16698931

    Open questions at the time
    • Splicing control machinery unidentified
    • Single lab
  10. 2006 Medium

    Linked DR3 promoter CpG hypermethylation to transcriptional silencing in RA synovial cells, a possible apoptosis-resistance mechanism.

    Evidence Bisulfite sequencing, methylation-specific PCR, luciferase promoter assay, forced Sss I methylation, Western blot

    PMID:16508942

    Open questions at the time
    • Causal contribution to RA pathology not established in vivo
    • Upstream trigger of methylation unknown
  11. 2008 High

    Established DR3 as the in vivo costimulatory receptor for effector T cell accumulation and cytokine production at inflamed sites, acting downstream of priming/polarization.

    Evidence DR3-deficient mice in EAE and allergic lung inflammation, flow cytometry, cytokine measurement, adoptive transfer

    PMID:18411337 PMID:18411341 PMID:18571443

    Open questions at the time
    • Molecular link between DR3 signaling and tissue accumulation incomplete
    • Relative contributions across T cell subsets not fully separated
  12. 2010 High

    Revealed an agonist-driven Treg expansion function dependent on TCR/MHC II, IL-2R, and Akt, opening DR3 as a Treg-targeting axis.

    Evidence Agonistic mAb 4C12 in mice with Akt/mTOR inhibitors, CD80/86 blockade, allergic lung model

    PMID:20890040

    Open questions at the time
    • Mechanism of Treg selectivity over conventional T cells unresolved
    • Durability of expanded Tregs not defined
  13. 2011 Medium

    Extended DR3 costimulation to CD8+ T cells, driving CTL differentiation and memory re-expansion.

    Evidence Ectopic TL1A on plasmacytomas, OT-I transgenic system, in vivo tumor challenge and memory re-expansion assays

    PMID:21688261

    Open questions at the time
    • Single lab
    • Signaling pathway in CD8+ cells not dissected
  14. 2013 Medium

    Defined the primary-T-cell signaling complex (TRADD/TRAF2) coupling DR3 to NF-κB and PI3K/Akt with TCR and IL-2R coordination.

    Evidence Co-IP in primary T cells, NF-κB reporter, PI3K/Akt assays, TCR/IL-2R signal blockade (review of authors' data)

    PMID:24242819

    Open questions at the time
    • Review-format summary of prior data
    • Stoichiometry and kinetics of complex not defined
  15. 2014 Medium

    Identified Atsttrin as a DR3 ligand-blocking molecule and mapped the first three CRDs as the binding region, providing an antagonist tool.

    Evidence Binding/domain-mapping with DR3 truncations, competitive TL1A-blocking assay, osteoclastogenesis assay, DSS colitis

    PMID:24651300

    Open questions at the time
    • Endogenous physiological relevance of Atsttrin-DR3 axis unclear
    • Single lab
  16. 2015 High

    Demonstrated cell-intrinsic DR3-driven Th9 generation via an IL-2/STAT5 pathway distinct from OX40/STAT6, refining subset-specific costimulation.

    Evidence DR3-deficient T cell Th9 differentiation, STAT5/STAT6 phospho assays, cytokine blockade, allergic lung model

    PMID:25786692

    Open questions at the time
    • Integration of DR3 with TCR signal strength for Th9 unclear
  17. 2016 Medium

    Established context-dependence of DR3 in transplantation: prophylactic activation expands suppressive Tregs and reduces GVHD, whereas activation during ongoing disease worsens donor T cell activation.

    Evidence Agonistic anti-DR3 in allogeneic HSCT model, immunophenotyping, in vivo suppression assays

    PMID:27760760

    Open questions at the time
    • Molecular basis of the timing-dependent switch unresolved
    • Single lab
  18. 2016 Medium

    Showed DR3 maintains intestinal Foxp3+ Tregs and protects against acute colitis and Salmonella, with loss skewing toward Th17.

    Evidence DR3-/- DSS colitis, TL1A-/- comparison, Salmonella infection, Treg/Th17 flow cytometry

    PMID:27233964

    Open questions at the time
    • Cell-type-specific requirement not fully separated
    • Single lab
  19. 2017 High

    Identified Galectin-9 as a DR3-binding partner partly required for DR3-driven Treg expansion and autoimmunity suppression.

    Evidence Direct binding assay, Co-IP in Tregs, Galectin-9-/- T cells in vitro, Galectin-9-/- mice in EAE and allergic lung models

    PMID:28877989

    Open questions at the time
    • How Galectin-9 modifies DR3 signaling biochemically unknown
    • Relationship to TL1A binding not fully defined
  20. 2017 Medium

    Connected DR3 to bone pathology and innate IFN-γ responses: DR3 enhances osteoclastogenesis (CCL3/MMP-9) in arthritis and, with IL-18R, supports non-cognate Th1 IFN-γ during bacterial infection.

    Evidence DR3-/- CIA with micro-CT, human CD14+ osteoclast assays; conditional T cell receptor KO and MyD88 T cell KO in multiple bacterial infections

    PMID:28062298 PMID:28817719

    Open questions at the time
    • Direct DR3 signaling pathway in osteoclast precursors not fully dissected
    • Single labs
  21. 2019 High

    Defined a DR3→p38 MAPK→GM-CSF→IL-23 axis in ILC3s controlling intestinal myeloid recruitment and ILC3 turnover.

    Evidence Agonistic anti-DR3 in mice, flow cytometry, p38 inhibition, GM-CSF/IL-23 neutralization, colitis models

    PMID:31358760

    Open questions at the time
    • Proximal coupling of DR3 to p38 in ILC3s unmapped
  22. 2020 High

    Extended DR3 function to innate and stromal cells: NF-κB-dependent ILC2 activation in adipose tissue improving glucose homeostasis, and direct Rho-pathway fibroblast signaling driving intestinal fibrosis.

    Evidence IL-33 induction and NF-κB assays in ILC2s with metabolic readouts; fibroblast-specific Dr3 deletion in colitis, fibroblast migration assays, RNA-seq, Rho inhibition

    PMID:32948777 PMID:33097818

    Open questions at the time
    • Biochemical link from DR3 to Rho activation undefined
    • Translation of metabolic findings to human untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single receptor's downstream complex composition is selected across cell types to choose among apoptosis, NF-κB, MAPK, PI3K/Akt, and Rho outputs remains unresolved.
  • No experimental structure of DR3 or its signaling complex
  • Cell-type determinants of complex assembly and output selection unknown
  • Mechanism of Treg-selective expansion not molecularly defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0098772 molecular function regulator activity 3 GO:0048018 receptor ligand activity 1
Localization
GO:0005886 plasma membrane 2
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 4 R-HSA-5357801 Programmed Cell Death 3
Partners
CASP8FADDLGALS9RIPK1TNFSF15TRADDTRAF2

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 DR3 (TNFRSF25) was identified as a death domain-containing TNF receptor family member that induces both apoptosis and NF-κB activation. Signal transduction is mediated by a complex of intracellular signaling molecules including TRADD, TRAF2, FADD, and FLICE (caspase-8). Molecular cloning, overexpression in cell lines, co-immunoprecipitation of signaling complex components, functional apoptosis and NF-κB activation assays Science High 8875942
1997 DR3 (LARD) undergoes alternative pre-mRNA splicing generating at least 11 distinct isoforms; the full-length isoform (LARD-1) contains transmembrane and death domains and induces spontaneous apoptosis when expressed in 293T cells, whereas other isoforms encode potentially secreted molecules. Upon T cell activation, a programmed switch in alternative splicing occurs so that the membrane-bound full-length form predominates. Molecular cloning, cDNA sequencing, overexpression in 293T cells with apoptosis readout, RT-PCR of splicing isoforms in lymphocyte subsets before and after activation Proceedings of the National Academy of Sciences of the United States of America High 9114039
1998 Caspase-8 is required for DR3-mediated cell death. In Caspase-8-null fibroblasts, DR3 retains the ability to activate JNK and trigger IκBα phosphorylation/degradation but fails to induce apoptosis, demonstrating that Caspase-8 is a necessary and non-redundant component of DR3-initiated death signaling. Homozygous targeted gene disruption (Casp8 knockout mice), fibroblast cell death assays, JNK activation assay, IκBα phosphorylation/degradation assay Immunity High 9729047
2001 DR3 plays a non-redundant role in negative selection of thymocytes. DR3-deficient mice show significantly impaired negative selection and anti-CD3-induced apoptosis, while superantigen-induced negative selection, positive selection, and the pre-TCR checkpoint remain normal. Genetic knockout (DR3-null mice), thymocyte apoptosis assays, negative selection assays with anti-CD3 and superantigen stimulation, positive selection analysis Molecular and cellular biology High 11313471
2002 TL1A (TNFSF15), an endothelial cell-derived TNF-family cytokine, is the ligand for DR3 and for decoy receptor TR6/DcR3. TL1A-DR3 interaction induces NF-κB activation and apoptosis in DR3-expressing cell lines, and TL1A costimulates T cells to increase IL-2 responsiveness and secretion of pro-inflammatory cytokines. Ligand-receptor binding assays, NF-κB activation reporter assays, apoptosis assays in DR3-expressing cell lines, T cell cytokine secretion assays, TR6-Fc antagonism experiments in vitro and in vivo Immunity High 11911831
2003 TL1A-DR3 interaction forms a signaling complex containing TRADD, TRAF2, and RIP and activates NF-κB as well as ERK, JNK, and p38 MAPK pathways. DR3-mediated NF-κB activation induces c-IAP2 production, which prevents DR3-mediated apoptosis; inhibition of c-IAP2 by RNA interference sensitizes cells to TL1A-induced apoptosis. FADD and procaspase-8 are absent from the TL1A-induced DR3 signaling complex in TF-1 cells. Co-immunoprecipitation of DR3 signaling complex, NF-κB reporter assay, MAPK kinase assays, pathway-specific inhibitors, RNA interference of c-IAP2, apoptosis assays in TF-1 cells The Journal of biological chemistry High 12882979
2005 DR3 and TNFR1 activate IL-8 gene transcription through distinct kinase cascades despite both receptors activating TRAF2 and NF-κB: DR3 uses the TAK1/ASK1–MKK4/MKK7–JNK2 axis, whereas TNFR1 uses the ASK1–MKK4–JNK1/JNK2/p38MAPK axis for IL-8 induction. Overexpression of DR3 and TNFR1 in HEK293 cells, dominant-negative kinase constructs, IL-8 reporter gene assays, TRAF2 and NF-κB pathway dissection Experimental cell research Medium 16324699
2006 During lymphocyte activation, alternative splicing of DR3 mRNA results in upregulation of the complete transmembrane (tm) form of DR3, which is the form responsible for TL1A-mediated costimulation of memory CD4+/CD45RBlo T cells and IFN-γ secretion. RT-PCR for DR3 mRNA isoforms in activated lymphocytes from mouse models of intestinal inflammation, in vitro T cell stimulation assays with TL1A, cytokine ELISA Proceedings of the National Academy of Sciences of the United States of America Medium 16698931
2000 TWEAK does not interact with DR3 (WSL-1/TRAMP) in in vitro binding assays; TWEAK binds strongly to cells lacking surface DR3, and DR3-knockout cells retain TWEAK responsiveness, establishing that DR3 is not the major functional receptor for TWEAK. In vitro binding assay with human and murine TWEAK and DR3, cell binding studies on DR3-negative cells, DR3 knockout mouse-derived cells FEBS letters Medium 11094155
2008 DR3 is required on T cells for immunopathology, local T cell accumulation, and cytokine production at sites of inflammation in EAE and allergic lung inflammation. DR3 is the receptor responsible for TL1A-induced T cell costimulation; dendritic cells are identified as the likely source of TL1A during T cell activation. DR3 is not required for T cell priming or polarization into Th1/Th2/Th17 subsets. DR3-deficient mouse generation, EAE and allergic lung inflammation models, flow cytometry of T cell subsets, cytokine measurement, adoptive transfer experiments Immunity High 18571443
2008 TNFR25 (DR3) signaling is required for Th2 effector function in Th2-polarized CD4 cells and for co-stimulation of IL-13 production by NKT cells in allergic lung inflammation. Blockade of TL1A (TNFSF15) or expression of a dominant-negative TNFR25 transgene inhibits lung inflammation and Th2 cytokine production in vivo. Antibody blockade of TL1A in vivo, dominant-negative TNFR25 transgenic mice, adoptive transfer of NKT cells (wild-type vs. DN-TNFR25 transgenic), IL-13 cytokine measurement, bronchoalveolar lavage analysis The Journal of experimental medicine High 18411341
2008 TL1A-DR3 signaling promotes proliferation of Th17 cells; TL1A-deficient dendritic cells have reduced capacity to support Th17 differentiation and proliferation. TL1A-deficient mice display decreased clinical severity in EAE, with reduced Th17 differentiation and effector function. TL1A-deficient mouse generation, EAE model, in vitro Th17 differentiation assays with TL1A−/− dendritic cells, flow cytometry of Th17 populations, cytokine analysis The Journal of experimental medicine High 18411337
2010 TNFR25 (DR3) signaling via agonistic monoclonal antibody 4C12 induces rapid and selective expansion of pre-existing Foxp3+ Tregs in vivo (up to 30-35% of CD4+ T cells within 4 days). This TNFR25-induced Treg proliferation depends on TCR engagement with MHC class II, IL-2 receptor signaling, and Akt signaling, but not CD80/CD86 co-stimulation or rapamycin. Agonistic monoclonal antibody treatment in mice (clone 4C12), flow cytometry of Treg populations, pharmacological inhibition of Akt and mTOR (rapamycin), blocking antibodies against CD80/CD86, allergic lung inflammation model The Journal of clinical investigation High 20890040
2011 TNFRSF25 functions as a costimulatory receptor for CD8+ T cells: TL1A-induced triggering of TNFRSF25 in vivo promotes proliferation and accumulation of antigen-specific CD8+ T cells and their differentiation into CTLs. TNFRSF25 also costimulates memory CD8+ T cell secondary expansion. Ectopic expression of TL1A on plasmacytomas, in vivo tumor challenge model, OT-I TCR transgenic T cell system, flow cytometry for T cell proliferation and CTL differentiation, in vivo memory CD8+ T cell re-expansion assay European journal of immunology Medium 21688261
2013 Ligation of TNFRSF25 (DR3) by TL1A leads to recruitment of TRAF2 and TRADD in primary T cells with downstream activation of both NF-κB and the PI3K/Akt signaling axis. These signaling pathways depend on coordinated engagement of the TCR and the IL-2 receptor. Co-immunoprecipitation of TRAF2 and TRADD with DR3 in primary T cells, NF-κB reporter assay, PI3K/Akt pathway activation assays, blocking of TCR and IL-2 receptor signals Immunologic research Medium 24242819
2014 Atsttrin (a progranulin-derived molecule) directly binds to DR3 (TNFRSF25); the first three cysteine-rich domains (CRDs) in the extracellular portion of DR3 are required for this interaction. Atsttrin inhibits the interaction between DR3 and TL1A and neutralizes TL1A-enhanced osteoclastogenesis in vitro. Direct binding assay (pulldown/ELISA-based screening), domain-mapping with DR3 truncation mutants, competitive binding assay (DR3-TL1A interaction blocked by Atsttrin), in vitro osteoclastogenesis assay, DSS-induced colitis model PloS one Medium 24651300
2015 TL1A promotes generation of IL-9-producing Th9 cells through DR3 in a cell-intrinsic manner; TL1A enhances Th9 differentiation via an IL-2 and STAT5-dependent mechanism, distinct from OX40-mediated Th9 induction (which requires IL-4 and STAT6). Endogenous DR3 signaling on T cells is required for maximal IL-9 production and pathology in allergic lung inflammation. In vitro Th9 differentiation assays with TL1A and DR3-deficient T cells, STAT5 and STAT6 phosphorylation assays, cytokine blocking experiments, DR3-deficient mouse allergic lung inflammation model, cytokine ELISA Journal of immunology High 25786692
2017 The extracellular region of DR3 directly binds to Galectin-9; Galectin-9 associates with DR3 in Tregs. DR3-induced stimulatory activity (Treg expansion and suppression of autoimmunity) is partially dependent on Galectin-9 in vitro and is lost in Galectin-9-deficient mice in EAE and allergic lung inflammation models. Direct binding assay (extracellular DR3 region and Galectin-9), co-immunoprecipitation of Galectin-9 with DR3 in Tregs, in vitro Treg stimulation with Galectin-9-/- T cells, in vivo EAE and allergic lung inflammation in Galectin-9-/- mice treated with DR3 agonist Journal of immunology High 28877989
2017 DR3 signaling in osteoclast precursors (CD14+ cells) enhances osteoclast differentiation and bone resorption via TL1A, with increased production of CCL3 and MMP-9. DR3 knockout protects mice against collagen-induced arthritis and associated systemic trabecular bone loss. DR3 knockout mouse CIA model with micro-CT analysis, in vitro osteoclast differentiation of human CD14+ precursors treated with TL1A, TRAP staining, bone resorption pit assay, CCL3/MMP-9 ELISA Bone Medium 28062298
2019 Activation of DR3 signaling by agonistic anti-DR3 antibody increases GM-CSF production from ILC3s through the p38 MAPK pathway, causing accumulation of eosinophils, neutrophils, and CD11b+CD11c+ myeloid cells, and resulting in IL-23-dependent loss of ILC3s from the intestine. Blockade of GM-CSF or IL-23 reverses anti-DR3-driven ILC3 loss. Agonistic anti-DR3 antibody treatment in mice, flow cytometry of intestinal ILC3s and myeloid cells, GM-CSF ELISA, p38 MAPK inhibitor experiments, GM-CSF and IL-23 neutralization, soluble DR3 (TL1A neutralization) in DSS and anti-CD40 colitis models Nature communications High 31358760
2020 Direct TL1A-DR3 signaling on fibroblasts promotes intestinal fibrosis in vivo. DR3 on fibroblasts is required for fibroblast activation and migration; deletion of DR3 specifically on fibroblasts reduces intestinal fibrosis without affecting clinical disease or inflammation. RNA-sequencing identified Rho signal transduction as a major pathway activated by TL1A in fibroblasts. T cell transfer colitis model in Rag-/-, Rag-/-Dr3-/-, and Rag-/-Dr3ΔCol1a2 mice; collagen deposition assay; fibroblast activation/migration assays in vitro; RNA-sequencing of TL1A-stimulated fibroblasts; Rho pathway inhibition Scientific reports High 33097818
2020 DR3 on visceral adipose tissue ILC2s is inducible by IL-33. DR3 engagement activates canonical and/or non-canonical NF-κB pathways in ILC2s, stimulating naïve and co-stimulating IL-33-activated ILC2s. DR3 stimulation of adipose ILC2s ameliorates glucose tolerance and reverses established insulin resistance in a type 2 diabetes model. Flow cytometry of DR3 expression on murine and human ILC2s, IL-33 induction experiments, NF-κB pathway activation assays (canonical and non-canonical), DR3 agonist treatment in vivo, glucose tolerance and insulin resistance assays Nature communications Medium 32948777
2005 Comparative structural modeling predicts that the DR3 (TNFRSF25) extracellular domain comprises four cysteine-rich domains (CRDs), and that a rheumatoid arthritis-linked D158G mutation eliminates two hydrogen bonds in a conserved motif at the end of CRD3, likely destabilizing the ligand-receptor complex. Comparative homology modeling of DR3 extracellular domain based on known TNF receptor crystal structures, energy minimization, structural analysis of RA-linked mutation sites Biochemical and biophysical research communications Low 15694416
2006 The DR3 gene promoter CpG island is specifically hypermethylated in rheumatoid arthritis synovial cells, and this hypermethylation inhibits DR3 gene transcription and reduces DR3 protein expression, potentially providing resistance to apoptosis in RA synovial cells. Bisulfite genomic sequencing, methylation-specific PCR, luciferase reporter promoter assay, forced methylation with bacterial Sss I methylase in vitro, Western blotting for DR3 protein Arthritis and rheumatism Medium 16508942
2016 DR3 signaling modulates the function of Foxp3+ Tregs; DR3-activated Tregs display an activated/mature phenotype and the CD25+Foxp3+ subpopulation shows stronger in vivo suppressive activity. The functional consequence of DR3 signaling is highly dependent on the activation status of T cells: prophylactic DR3 activation expands recipient Tregs and reduces GVHD severity, while DR3 activation during ongoing GVHD further promotes donor T cell activation. Agonistic anti-DR3 antibody treatment of donor and recipient mice, allogeneic hematopoietic stem cell transplantation model, flow cytometry immunophenotyping, in vivo suppression assays Blood Medium 27760760
2016 DR3 is required for intact TL1A/DR3 signaling in protection against acute intestinal injury: DR3-/- mice show more severe DSS colitis, increased mortality, and compromised maintenance of Foxp3+ Tregs, leading to non-specific upregulation of Th17 effector responses. DR3-/- mice also show defective Salmonella clearance with elevated bacterial load. DR3-deficient mouse DSS colitis model, TL1A-deficient mouse comparison, Salmonella typhimurium infection, flow cytometry of Treg and Th17 populations, cytokine analysis Journal of immunology Medium 27233964
2017 CD4 Th1 cell expression of both IL-18R and DR3 is required for optimal IFN-γ induction in response to non-cognate (TCR-independent) stimulation during Salmonella infection. T cell-intrinsic MyD88 (a DR3 adapter) is required for efficient bacterial clearance from Salmonella, Chlamydia, and Brucella infections. Conditional T cell-specific receptor knockout mice, non-cognate Th1 stimulation assay in Salmonella-infected mice, IFN-γ ELISA, MyD88 T cell-specific KO mice infected with multiple intracellular bacteria, bacterial burden quantification PLoS pathogens Medium 28817719

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 Targeted disruption of the mouse Caspase 8 gene ablates cell death induction by the TNF receptors, Fas/Apo1, and DR3 and is lethal prenatally. Immunity 1006 9729047
1996 Signal transduction by DR3, a death domain-containing receptor related to TNFR-1 and CD95. Science (New York, N.Y.) 541 8875942
2002 TL1A is a TNF-like ligand for DR3 and TR6/DcR3 and functions as a T cell costimulator. Immunity 526 11911831
2008 TL1A-DR3 interaction regulates Th17 cell function and Th17-mediated autoimmune disease. The Journal of experimental medicine 187 18411337
2008 The TNF-family receptor DR3 is essential for diverse T cell-mediated inflammatory diseases. Immunity 180 18571443
1997 LARD: a new lymphoid-specific death domain containing receptor regulated by alternative pre-mRNA splicing. Proceedings of the National Academy of Sciences of the United States of America 175 9114039
2011 Structure of the full human RXR/VDR nuclear receptor heterodimer complex with its DR3 target DNA. The EMBO journal 160 22179700
2008 Essential role of TNF receptor superfamily 25 (TNFRSF25) in the development of allergic lung inflammation. The Journal of experimental medicine 153 18411341
2006 Role of TL1A and its receptor DR3 in two models of chronic murine ileitis. Proceedings of the National Academy of Sciences of the United States of America 137 16698931
2010 Therapeutic Treg expansion in mice by TNFRSF25 prevents allergic lung inflammation. The Journal of clinical investigation 132 20890040
1998 A male-female bias in type 1 diabetes and linkage to chromosome Xp in MHC HLA-DR3-positive patients. Nature genetics 115 9662410
2014 High-lard and high-fish-oil diets differ in their effects on function and dynamic behaviour of rat hepatic mitochondria. PloS one 114 24663492
2011 TL1A and DR3, a TNF family ligand-receptor pair that promotes lymphocyte costimulation, mucosal hyperplasia, and autoimmune inflammation. Immunological reviews 106 22017439
2003 TL1A-induced NF-kappaB activation and c-IAP2 production prevent DR3-mediated apoptosis in TF-1 cells. The Journal of biological chemistry 105 12882979
2002 Liganded VDR induces CYP3A4 in small intestinal and colon cancer cells via DR3 and ER6 vitamin D responsive elements. Biochemical and biophysical research communications 97 12470639
2015 The TNF-family ligand TL1A and its receptor DR3 promote T cell-mediated allergic immunopathology by enhancing differentiation and pathogenicity of IL-9-producing T cells. Journal of immunology (Baltimore, Md. : 1950) 96 25786692
2006 Hypermethylated promoter region of DR3, the death receptor 3 gene, in rheumatoid arthritis synovial cells. Arthritis and rheumatism 96 16508942
2019 TL1A (TNFSF15) and DR3 (TNFRSF25): A Co-stimulatory System of Cytokines With Diverse Functions in Gut Mucosal Immunity. Frontiers in immunology 93 30972074
2001 DR3 regulates negative selection during thymocyte development. Molecular and cellular biology 86 11313471
1998 Haplotype HLA-B8-DR3 confers susceptibility to hepatitis C virus-related mixed cryoglobulinemia. Blood 76 9490691
2013 Anti-cancer effect and apoptosis induction of cordycepin through DR3 pathway in the human colonic cancer cell HT-29. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 73 23941773
1994 HLA-DR3 molecules can bind peptides carrying two alternative specific submotifs. Journal of immunology (Baltimore, Md. : 1950) 73 8207204
2016 Identification of pork flavour precursors from enzyme-treated lard using Maillard model system assessed by GC-MS and partial least squares regression. Meat science 72 27792915
2011 Upregulation and nuclear localization of TNF-like cytokine 1A (TL1A) and its receptors DR3 and DcR3 in psoriatic skin lesions. Experimental dermatology 72 21672030
2005 Involvement of TL1A and DR3 in induction of pro-inflammatory cytokines and matrix metalloproteinase-9 in atherogenesis. Cytokine 71 15760679
1999 Early expression and high prevalence of islet autoantibodies for DR3/4 heterozygous and DR4/4 homozygous offspring of parents with Type I diabetes: the German BABYDIAB study. Diabetologia 70 10382586
1983 HLA-DR3 and DR7 in coeliac disease: immunogenetic and clinical aspects. Gut 64 6603391
2024 Quinic acid alleviates high-fat diet-induced neuroinflammation by inhibiting DR3/IKK/NF-κB signaling via gut microbial tryptophan metabolites. Gut microbes 63 38972055
2014 Progranulin-derived Atsttrin directly binds to TNFRSF25 (DR3) and inhibits TNF-like ligand 1A (TL1A) activity. PloS one 59 24651300
2013 The role of TL1A and DR3 in autoimmune and inflammatory diseases. Mediators of inflammation 59 24453414
1985 HLA class II regulation and structure. Analysis with HLA-DR3 and HLA-DP point mutants. The Journal of experimental medicine 58 2413154
2011 Triggering of TNFRSF25 promotes CD8⁺ T-cell responses and anti-tumor immunity. European journal of immunology 56 21688261
2020 The Role of the TL1A/DR3 Axis in the Activation of Group 2 Innate Lymphoid Cells in Subjects with Eosinophilic Asthma. American journal of respiratory and critical care medicine 55 32584596
2019 Activation of DR3 signaling causes loss of ILC3s and exacerbates intestinal inflammation. Nature communications 54 31358760
1985 HLA A1-B8-DR3 and suppressor cell function in first-degree relatives of patients with autoimmune chronic active hepatitis. Journal of hepatology 53 2933448
2019 Influence of lard-based diacylglycerol on rheological and physicochemical properties of thermally induced gels of porcine myofibrillar protein at different NaCl concentrations. Food research international (Ottawa, Ont.) 52 31882115
2017 Regulatory T Cell-Mediated Suppression of Inflammation Induced by DR3 Signaling Is Dependent on Galectin-9. Journal of immunology (Baltimore, Md. : 1950) 50 28877989
2012 Differential effects of high-fat-diet rich in lard oil or soybean oil on osteopontin expression and inflammation of adipose tissue in diet-induced obese rats. European journal of nutrition 49 22847642
2002 Common HLA-B8-DR3 haplotype in Northern India is different from that found in Europe. Tissue antigens 49 12542740
2017 Fish oil, lard and soybean oil differentially shape gut microbiota of middle-aged rats. Scientific reports 47 28400577
2005 Genotoxicity and oxidative stress of the mutagenic compounds formed in fumes of heated soybean oil, sunflower oil and lard. Toxicology in vitro : an international journal published in association with BIBRA 47 16216463
2000 Studies on the interaction between TWEAK and the death receptor WSL-1/TRAMP (DR3). FEBS letters 46 11094155
2016 Properties and oxidative stability of emulsions prepared with myofibrillar protein and lard diacylglycerols. Meat science 45 26775153
2015 Tumor Necrosis Factor-like Cytokine TL1A and Its Receptors DR3 and DcR3: Important New Factors in Mucosal Homeostasis and Inflammation. Inflammatory bowel diseases 45 26099067
2006 Conserved extended haplotypes discriminate HLA-DR3-homozygous Basque patients with type 1 diabetes mellitus and celiac disease. Genes and immunity 45 16929349
2016 DR3 signaling modulates the function of Foxp3+ regulatory T cells and the severity of acute graft-versus-host disease. Blood 40 27760760
2015 Human group3 innate lymphoid cells express DR3 and respond to TL1A with enhanced IL-22 production and IL-2-dependent proliferation. European journal of immunology 40 26046454
2016 Effects of an High-Fat Diet Enriched in Lard or in Fish Oil on the Hypothalamic Amp-Activated Protein Kinase and Inflammatory Mediators. Frontiers in cellular neuroscience 39 27375435
2015 The TL1A/DR3/DcR3 pathway in autoimmune rheumatic diseases. Seminars in arthritis and rheumatism 39 25887448
1986 Altered phagocytosis by monocytes from HLA-DR2 and DR3-positive healthy adults is Fc gamma receptor specific. Journal of immunology (Baltimore, Md. : 1950) 38 3009607
2016 A Novel Role for TL1A/DR3 in Protection against Intestinal Injury and Infection. Journal of immunology (Baltimore, Md. : 1950) 37 27233964
2012 Changes in glucose tolerance and leptin responsiveness of rats offered a choice of lard, sucrose, and chow. American journal of physiology. Regulatory, integrative and comparative physiology 37 22496363
2012 Tregs expanded in vivo by TNFRSF25 agonists promote cardiac allograft survival. Transplantation 37 22902792
2000 Co-expression of HLA DR3 and DQ8 results in the development of spontaneous insulitis and loss of tolerance to GAD65 in transgenic mice. Diabetes 37 10871191
2025 Targeting TL1A and DR3: the new frontier of anti-cytokine therapy in IBD. Gut 36 39266053
2013 Immunobiology of TNFSF15 and TNFRSF25. Immunologic research 35 24242819
1988 Ro(SS-A) positive Sjogren's/lupus erythematosus (SC/LE) overlap patients are associated with the HLA-DR3 and/or DRw6 phenotypes. The Journal of investigative dermatology 35 3262691
2016 Physicochemical and structural properties of composite gels prepared with myofibrillar protein and lard diacylglycerols. Meat science 34 27420798
1995 T-cell activation in HLA-B8, DR3-positive individuals. Early antigen expression defect in vitro. Human immunology 34 7558912
2020 Direct signaling of TL1A-DR3 on fibroblasts induces intestinal fibrosis in vivo. Scientific reports 33 33097818
1999 HLA associations in type 1 diabetes among patients not carrying high-risk DR3-DQ2 or DR4-DQ8 haplotypes. Tissue antigens 33 10674967
2013 Differential responses of hepatic endoplasmic reticulum stress and inflammation in diet-induced obese rats with high-fat diet rich in lard oil or soybean oil. PloS one 32 24223162
1992 The evolutionary origin of the HLA-DR3 haplotype. Immunogenetics 32 1541486
2020 DR3 stimulation of adipose resident ILC2s ameliorates type 2 diabetes mellitus. Nature communications 30 32948777
2012 T cell costimulation by TNFR superfamily (TNFRSF)4 and TNFRSF25 in the context of vaccination. Journal of immunology (Baltimore, Md. : 1950) 30 22956587
2009 HLA-DQ8 (DQB1*0302)-restricted Th17 cells exacerbate experimental autoimmune encephalomyelitis in HLA-DR3-transgenic mice. Journal of immunology (Baltimore, Md. : 1950) 29 19342694
2004 Death receptor 3 (DR3) gene duplication in a chromosome region 1p36.3: gene duplication is more prevalent in rheumatoid arthritis. Genes and immunity 29 15241467
1991 DR3 and nonDR3 associated complement component C4A deficiency in systemic lupus erythematosus. Clinical immunology and immunopathology 29 2044237
2017 CCL3 and MMP-9 are induced by TL1A during death receptor 3 (TNFRSF25)-dependent osteoclast function and systemic bone loss. Bone 28 28062298
2017 T cell expression of IL-18R and DR3 is essential for non-cognate stimulation of Th1 cells and optimal clearance of intracellular bacteria. PLoS pathogens 27 28817719
1998 Duplication of the DR3 gene on human chromosome 1p36 and its deletion in human neuroblastoma. Genomics 27 9615223
2022 Intralymphatic GAD-Alum (Diamyd®) Improves Glycemic Control in Type 1 Diabetes With HLA DR3-DQ2. The Journal of clinical endocrinology and metabolism 26 35665810
2004 Graves' hyperthyroidism and thyroiditis in HLA-DRB1*0301 (DR3) transgenic mice after immunization with thyrotropin receptor DNA. Clinical and experimental immunology 26 14678262
2011 HLA-DR3 restricted T cell epitope mimicry in induction of autoimmune response to lupus-associated antigen SmD. Journal of autoimmunity 25 21868195
2005 Hepatic vagotomy alters limbic and hypothalamic neuropeptide responses to insulin-dependent diabetes and voluntary lard ingestion. The European journal of neuroscience 24 15926921
2003 Heterozygosity for MICA5.0/MICA5.1 and HLA-DR3-DQ2/DR4-DQ8 are independent genetic risk factors for latent autoimmune diabetes in adults. Human immunology 24 12941547
2012 TNFRSF25 agonistic antibody and galectin-9 combination therapy controls herpes simplex virus-induced immunoinflammatory lesions. Journal of virology 23 22811539
2022 The Lard Works in Mysterious Ways: Ceramides in Nutrition-Linked Chronic Disease. Annual review of nutrition 22 35584813
2019 Naturally processed HLA-DR3-restricted HHV-6B peptides are recognized broadly with polyfunctional and cytotoxic CD4 T-cell responses. European journal of immunology 22 31020640
1995 Transcomplementation of HLA DQA1-DQB1 in DR3/DR4 and DR3/DR9 heterozygotes and IDDM in Taiwanese families. Diabetes care 22 8722074
2005 Differential regulation of interleukin-8 gene transcription by death receptor 3 (DR3) and type I TNF receptor (TNFRI). Experimental cell research 21 16324699
2003 Expression and function of HLA-DR3 and DQ8 in transgenic mice lacking functional H2-M. Tissue antigens 21 12889995
1983 HLA-DR3- and HLA-DR7-restricted T-cell hyporesponsiveness to gluten antigen: a clue to the aetiology of coeliac disease? Scandinavian journal of immunology 21 6603652
2022 The TL1A-DR3 Axis in Asthma: Membrane-Bound and Secreted TL1A Co-Determined the Development of Airway Remodeling. Allergy, asthma & immunology research 20 35255540
2022 TL1A/DR3 Axis, A Key Target of TNF-a, Augments the Epithelial-Mesenchymal Transformation of Epithelial Cells in OVA-Induced Asthma. Frontiers in immunology 20 35359966
2020 Cepharanthine blocks TSH receptor peptide presentation by HLA-DR3: Therapeutic implications to Graves' disease. Journal of autoimmunity 20 31980336
2019 Ultrasound-mediated interfacial protein adsorption and fat crystallization in cholesterol-reduced lard emulsion. Ultrasonics sonochemistry 20 31450308
2009 Differential responses to Smith D autoantigen by mice with HLA-DR and HLA-DQ transgenes: dominant responses by HLA-DR3 transgenic mice with diversification of autoantibodies to small nuclear ribonucleoprotein, double-stranded DNA, and nuclear antigens. Journal of immunology (Baltimore, Md. : 1950) 20 20007529
2002 A 320-kilobase artificial chromosome encoding the human HLA DR3-DQ2 MHC haplotype confers HLA restriction in transgenic mice. Journal of immunology (Baltimore, Md. : 1950) 20 11884478
2002 Modulation of insulitis and type 1 diabetes by transgenic HLA-DR3 and DQ8 in NOD mice lacking endogenous MHC class II. Human immunology 20 12392851
2019 Activation of the DR3-TL1A Axis in Donor Mice Leads to Regulatory T Cell Expansion and Activation With Reduction in Graft-Versus-Host Disease. Frontiers in immunology 19 31379829
2020 Comparative study of dietary fat: lard and sugar as a better obesity and metabolic syndrome mice model. Archives of physiology and biochemistry 18 33176505
2019 Genetic Variation Within the HLA-DRA1 Gene Modulates Susceptibility to Type 1 Diabetes in HLA-DR3 Homozygotes. Diabetes 18 30962219
1992 Association of DR3 with susceptibility to and severity of primary Sjögren's syndrome in a family study. British journal of rheumatology 18 1581772
2022 Different Effects of Lard and Vegetable Blend Oil on Intestinal Microorganisms, Enzyme Activity and Blood Routine in Mice. Journal of oleo science 17 35034939
2022 A Lard and Soybean Oil Mixture Alleviates Low-Fat-High-Carbohydrate Diet-Induced Nonalcoholic Fatty Liver Disease in Mice. Nutrients 17 35276916
2018 Association of HLA-DR3 and HLA-DR15 Polymorphisms with Risk of Systemic Lupus Erythematosus. Chinese medical journal 17 30511687
2016 Biologics beyond TNF-α inhibitors and the effect of targeting the homologues TL1A-DR3 pathway in chronic inflammatory disorders. Immunopharmacology and immunotoxicology 17 26810853
2005 Comparative modeling of TNFRSF25 (DR3) predicts receptor destabilization by a mutation linked to rheumatoid arthritis. Biochemical and biophysical research communications 17 15694416
2003 Thyrotropin receptor-DNA vaccination of transgenic mice expressing HLA-DR3 or HLA-DQ6b. Thyroid : official journal of the American Thyroid Association 17 14611699

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