The Death Receptor 3–TNF-like protein 1A pathway drives adverse bone pathology in inflammatory arthritis

Bull, M; Williams, Anwen Siân; Mecklenburgh, Zarabeth; Calder, Claudia J.; Twohig, Jason Peter; Elford, Carole; Evans, Bronwen Alice James; Rowley, Tania F.; Ślebioda, Tomasz Jerzy; Taraban, Vadim Y.; Al‐Shamkhani, Aymen; Wang, Edward Chung Yern

doi:10.1084/jem.20072378

Cited by 99 publications

(146 citation statements)

References 34 publications

(42 reference statements)

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“…TNFSF15:DR3 signaling exacerbates inflammatory diseases in mice, including experimental colitis (10) and arthritis (37). TNFSF15 is elevated in intestinal tissues and serum of IBD patients (38,39).…”

Section: Discussionmentioning

confidence: 99%

A TNFSF15 disease-risk polymorphism increases pattern-recognition receptor-induced signaling through caspase-8–induced IL-1

Hedl

Abraham

2014

Proc. Natl. Acad. Sci. U.S.A.

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Inflammatory diseases are characterized by dysregulated cytokine production. Altered functions for most risk loci, including the inflammatory bowel disease and leprosy-associated tumor necrosis factor ligand superfamily member 15 (TNFSF15) region, are unclear. Regulation of pattern-recognition-receptor (PRR)-induced signaling and cytokines is crucial for immune homeostasis; TNFSF15:death receptor 3 (DR3) contributions to PRR responses have not been described. We found that human macrophages expressed DR3 and that TNFSF15:DR3 interactions were critical for amplifying PRR-initiated MAPK/NF-κB/PI3K signaling and cytokine secretion in macrophages. Mechanisms mediating TNFSF15:DR3 contributions to PRR outcomes included TACE-induced TNFSF15 cleavage to soluble TNFSF15; soluble TNFSF15 then led to TRADD/FADD/MALT-1-and caspase-8-mediated autocrine IL-1 secretion. Notably, TNFSF15 treatment also induced cytokine secretion through a caspase-8-dependent pathway in intestinal myeloid cells. Importantly, rs6478108 A disease risk-carrier macrophages demonstrated increased TNFSF15 expression and PRR-induced signaling and cytokines. Taken together, TNFSF15:DR3 interactions amplify PRR-induced signaling and cytokines, and the rs6478108 TNFSF15 disease-risk polymorphism results in a gain of function.Crohn disease | ulcerative colitis | genetics | NOD2 | TLR

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Section: Discussionmentioning

confidence: 99%

A TNFSF15 disease-risk polymorphism increases pattern-recognition receptor-induced signaling through caspase-8–induced IL-1

Hedl

Abraham

2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Sections (10 mm) were fixed in acetone, blocked with 5% goat serum and incubated with unconjugated or biotinylated rat (IgG) anti-TL1A [9] followed by Alexa Fluor 546-conjugated-goat anti-rat IgG or streptavidin (Molecular Probes, Invitrogen, UK). Sections were co-labelled with anti-CD11c (in house), anti-B220 (BD Pharmingen, UK) or anti-F4/80 (AbD Serotec, UK), followed by the appropriate Alexa Fluor-conjugated secondary antibodies (Molecular Probes, Invitrogen, UK).…”

Section: Microscopymentioning

confidence: 99%

“…42: 580-588 580 contains a death domain that binds to TRADD (TNFR1-associated death domain protein), a component of the TNFR1 signalosome that is capable of recruiting pro-caspase 8 as well as activating NF-kB [7]. Unlike TNFR1 however, which is widely expressed, expression of DR3 is limited primarily to T cells, cells of the monocyte/macrophage lineage and lymphoid tissue inducer (LTi) cells [8][9][10]. DR3 interacts with TL1A (TNFSF15), a TNF-like protein that is expressed on activated macrophages, dendritic cells, T cells and endothelial cells and is produced either as a membrane-anchored protein or a soluble cytokine [5,11,12].…”

Section: Introductionmentioning

confidence: 99%

Death receptor 3 is essential for generating optimal protective CD4¹ T‐cell immunity against Salmonella

et al. 2012

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The TNF receptor superfamily member death receptor 3 (DR3) exacerbates Th2-and Th17-cell-mediated inflammatory and autoimmune conditions, yet no role in host defence has been reported. Here, we examined the role of DR3 during infection with Salmonella enterica serovar Typhimurium. Infection resulted in protracted expression of the DR3 ligand TL1A but not the related TNF superfamily proteins OX40L or CD30L. TL1A expression was localized to splenic F4/80 1 macrophages where S. enterica Typhimurium replicates, and temporally coincided with the onset of CD4 1 -cell expansion. To address the relevance of the TL1A-DR3 interaction, we examined immune responses to S. enterica Typhimurium in mice lacking DR3. Infected DR3 À/À mice harboured reduced numbers of antigen-experienced and proliferating CD4 1 T cells compared with WT mice. Furthermore, the frequency of IFN-c 1 CD4 1 T cells in DR3 À/À mice was lower throughout the time of bacterial clearance. Importantly, bacterial clearance, which is dependent on Th1 cells, was also impaired in DR3 À/À mice. This defect was intrinsic to CD4 1 T cells as evidenced by an increase in bacterial burden in RAG2-deficient mice receiving DR3 À/À CD4 1 T cells compared with WT CD4 1 -cell recipients. These data establish for the first time a role for DR3 in a host defence response.Key words: Costimulation . DR3 . Th1 cells . TNF receptor superfamily . TNFRSF25 Supporting Information available online IntroductionMembers of the tumour necrosis factor receptor superfamily (TNFRSF), such as CD27, CD30, OX40 and 4-1BB, are key players in the regulation of T-cell-mediated immune responses [1,2]. Collectively, these receptors provide costimulatory signals to antigen-stimulated T cells that enhance their expansion and survival. Thus, costimulation by various members of the TNFRSF augments the magnitude of the primary and/or secondary T-cell response and contributes to host protection against infection [3,4]. The involvement of different TNFRSF members in regulating T-cell responses varies however, with some TNFRSF members contributing preferentially towards enhanced memory generation [3] or local responses within the inflamed tissue [5]. The requirement for multiple TNFRSF members probably arises due to distinct temporal patterns of costimulatory receptor and ligand expression, which are likely to be controlled by factors such as pathogen type and virulence [4,6].Death receptor 3 (DR3, TNFRSF25) is a member of the TNFRSF that is most similar in sequence to TNFR1 [7]. DR3 Eur. J. Immunol. 2012. 42: 580-588 580 contains a death domain that binds to TRADD (TNFR1-associated death domain protein), a component of the TNFR1 signalosome that is capable of recruiting pro-caspase 8 as well as activating NF-kB [7]. Unlike TNFR1 however, which is widely expressed, expression of DR3 is limited primarily to T cells, cells of the monocyte/macrophage lineage and lymphoid tissue inducer (LTi) cells [8][9][10]. DR3 interacts with TL1A (TNFSF15), a TNF-like protein that is expressed on activated macrophages,...

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“…J558L plasmacytoma cells originally derived from BALB/c mice were obtained from the European Collection of Cell Cultures and J558L cells expressing TL1A were described previously [16]. Soluble recombinant TL1A (sTL1A) was produced as a fusion protein with domains 3 and 4 of rat CD4 in CHO cells using previously described methods [17].…”

Section: Cells and Reagentsmentioning

confidence: 99%

“…Briefly, DNA encoding the extracellular domain of mouse TL1A (amino acids 77-252) was cloned downstream of the sequence encoding the leader peptide and domains 3 and 4 of rat CD4 in the expression vector pEE14 [17]. Anti-TL1A mAb (TAN2-2) was described previously [16], and biotinylated anti-TNFRSF25 Ab was obtained from R&D Systems. PE-labeled K b OVA 257-264 tetramer was produced by the Cancer Sciences Division Protein Expression Facility.…”

Section: Cells and Reagentsmentioning

confidence: 99%

Triggering of TNFRSF25 promotes CD8⁺ T‐cell responses and anti‐tumor immunity

et al. 2011

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TNFRSF25 is a member of the TNF receptor superfamily (TNFRSF) that binds to the TNFlike protein TL1A. Although recent studies have demonstrated a role for TNFRSF25 in regulating CD41 T-cell responses, it remains to be determined if TNFRSF25 functions as a costimulatory receptor for CD8 1 T cells. Here, we demonstrate that ectopic expression of TL1A on mouse plasmacytomas promotes elimination of tumor cells in a CD8 1 T-celldependent manner and renders mice immune to a subsequent challenge with tumor cells.To gain further insight into the role of TNFRSF25 in CD8 1 T-cell responses, we analyzed the effect of TNFRSF25 triggering on OT-I TCR transgenic T cells. We demonstrate that TNFRSF25 triggering in vivo with soluble TL1A promotes the proliferation and accumulation of antigen-specific CD8 1 T cells as well as their differentiation into CTLs. Furthermore, we show that TNFRSF25 also functions as a costimulatory receptor for memory CD8 1 T cells. Thus, TNFRSF25 triggering enhances the secondary expansion of endogenous antigen-specific memory CD8 1 T cells. Our data suggest that TNFRSF25 agonists, such as soluble TL1A, could potentially be used to enhance the immunogenicity of vaccines that aim to elicit human anti-tumor CD8 1 T cells. Results and discussionEctopic expression of TL1A-mediates CD8 1 T-celldependent rejection of J558L tumorsThree transfected J558L tumor cell lines that express relatively high levels of TL1A (Fig. 1A) were combined immediately before inoculation into mice. In T-and B-cell-deficient SCID mice TL1A-expressing J558L tumor cells grew with similar kinetics to control J558L cells transfected with the empty vector (Fig. 1B). In sharp contrast, TL1A-expressing J558L cells, but not control tumor cells, were rejected in immune competent BALB/c mice, demonstrating that tumor rejection requires an adaptive immune response (Fig. 1C). In many cases, TL1A-expressing J558L tumors grew initially following s.c. injection into BALB/c mice, but these tumors regressed and the majority of animals had no detectable tumors 70 days after initial tumor inoculation (Fig. 1C). Mice that rejected the TL1A-expressing J558L tumors were immune to a subsequent challenge with non-transfected J558L tumor cells ( Fig. 1D and Supporting Information Fig. 1A). To assess the role of T-cell subsets in TL1A-mediated tumor rejection, we administered anti-CD4 or anti-CD8 depleting mAbs prior to inoculation with TL1A-expressing J558L tumor cells. Only depletion of CD8 1 T cells resulted in a significant and consistent prevention of tumor cell rejection ( Fig. 1E and Supporting Information Fig. 1B). These results demonstrate that ectopic expression of TL1A can lead to the generation of a protective anti-tumor immune response and implicate a role for TNFRSF25 on CD8 1 T cells in mediating this effect.TNFRSF25 triggering costimulates Ag-specific CD8 1 T cells in vitroTo define more precisely the role of TNFRSF25 triggering in CD8 1 T-cell responses, we used OVA-specific TCR transgenic OT-IT cells as a model to study the effects of ...

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The Death Receptor 3–TNF-like protein 1A pathway drives adverse bone pathology in inflammatory arthritis

Cited by 99 publications

References 34 publications

A TNFSF15 disease-risk polymorphism increases pattern-recognition receptor-induced signaling through caspase-8–induced IL-1

A TNFSF15 disease-risk polymorphism increases pattern-recognition receptor-induced signaling through caspase-8–induced IL-1

Death receptor 3 is essential for generating optimal protective CD4¹ T‐cell immunity against Salmonella

Triggering of TNFRSF25 promotes CD8⁺ T‐cell responses and anti‐tumor immunity

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The Death Receptor 3–TNF-like protein 1A pathway drives adverse bone pathology in inflammatory arthritis

Cited by 99 publications

References 34 publications

A TNFSF15 disease-risk polymorphism increases pattern-recognition receptor-induced signaling through caspase-8–induced IL-1

A TNFSF15 disease-risk polymorphism increases pattern-recognition receptor-induced signaling through caspase-8–induced IL-1

Death receptor 3 is essential for generating optimal protective CD41 T‐cell immunity against Salmonella

Triggering of TNFRSF25 promotes CD8+ T‐cell responses and anti‐tumor immunity

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Product

Resources

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Death receptor 3 is essential for generating optimal protective CD4¹ T‐cell immunity against Salmonella

Triggering of TNFRSF25 promotes CD8⁺ T‐cell responses and anti‐tumor immunity