Death receptor 3 is essential for generating optimal protective CD4(+) T-cell immunity against Salmonella.
ABSTRACT The TNF receptor superfamily member death receptor 3 (DR3) exacerbates Th2 and Th17-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(+) macrophages where S. enterica Typhimurium replicates, and temporally coincided with the onset of CD4(+) -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(-/-) mice harboured reduced numbers of antigen-experienced and proliferating CD4(+) T cells compared with wild-type mice. Furthermore, the frequency of IFN-ã(+) CD4(+) T cells in DR3(-/-) mice was lower throughout the time of bacterial clearance. Importantly, bacterial clearance, which is dependent on Th1 cells, was also impaired in DR3(-/-) mice. This defect was intrinsic to CD4(+) T cells as evidenced by an increase in bacterial burden in RAG2-deficient mice receiving DR3(-/-) CD4(+) T cells compared with wild-type CD4(+) -cell recipients. These data establish for the first time a role for DR3 in a host defence response.
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ABSTRACT: Atsttrin, a progranulin (PGRN)-derived molecule composed of three TNFR-binding domains of PGRN, binds to TNF receptors (TNFR) and is therapeutic against inflammatory arthritis. Here we screened the associations of Atsttrin and other members in TNFR subfamily, which led to the discovery of TNFRSF25 (DR3) as an additional Atsttrin-interacting member in TNFR family. Similar to TNFR1 and TNFR2, DR3 also directly bound to Atsttrin. The first three cysteine-rich domains (CRD) in the extracellular portion of DR3 were required for this interaction. Atsttrin inhibited the interaction between DR3 and its TNF-Like Ligand 1A (TL1A). In addition, Atsttrin inhibited TL1A-stimulated target gene expressions and neutralized TL1A-enhanced osteoclastogenesis in vitro. Furthermore, Atsttrin ameliorated the pathology in dextran sulfate sodium induced colitis. Taken together, these findings not only provide the new insights into Atsttrin's therapeutic action in inflammatory arthritis, but may also present Atsttrin as a novel biological agent for treating various types of diseases associated with TL1A/DR3 pathway.PLoS ONE 03/2014; 9(3):e92743. · 3.53 Impact Factor
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ABSTRACT: Objectives: To investigate the role of Death Receptor 3 (DR3) and its ligand TNF-like protein 1A (TL1A) in early stages of inflammatory arthritis.Methods: C57BL/6 mice genetically deficient in the DR3 gene (DR3KO) and their DR3WT littermates were subjected to antigen-induced arthritis (AIA) by priming and intra-articular injection of methylated BSA. Joints were sectioned and analyzed histochemically for damage to cartilage and expression of DR3, TL1A, Ly6G (a marker for neutrophils), the gelatinase matrix metallopeptidase 9 (MMP-9), the aggrecanase a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS-5) and the neutrophil chemoattractant CXCL1. In vitro production of MMP-9 was measured from cultures of fibroblasts, macrophages and neutrophils following addition of TL1A and other pro-inflammatory stimuli.Results: DR3 expression was upregulated in the joint following induction of AIA in DR3WT mice. DR3KO mice were protected from cartilage damage compared to DR3WT mice, even at early timepoints prior to the main accumulation of effector T cells in the joint. Early protection from AIA in vivo correlated with reduced levels of MMP-9. In vitro, neutrophils were found to be major producers of MMP-9, while in vivo neutrophil numbers were reduced in DR3KO joints. However, TL1A neither induced MMP-9 release, nor affected survival of, neutrophils. Instead, reduced levels of CXCL1 were recorded in DR3KO joints.Conclusions: DR3 drives early cartilage destruction in the AIA model of inflammatory arthritis through the release of CXCL1, maximizing neutrophil recruitment to the joint leading to enhanced local production of cartilage destroying enzymes. © 2014 American College of Rheumatology.Arthritis & Rheumatology. 06/2014;
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ABSTRACT: Mucosal tissues contain large numbers of memory CD4(+) T cells that, through T-cell receptor-dependent interactions with antigen-presenting cells, are believed to have a key role in barrier defense and maintenance of tissue integrity. Here we identify a major subset of memory CD4(+) T cells at barrier surfaces that coexpress interleukin-18 receptor alpha (IL-18Rα) and death receptor-3 (DR3), and display innate lymphocyte functionality. The cytokines IL-15 or the DR3 ligand tumor necrosis factor (TNF)-like cytokine 1A (TL1a) induced memory IL-18Rα(+)DR3(+)CD4(+) T cells to produce interferon-γ, TNF-α, IL-6, IL-5, IL-13, granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-22 in the presence of IL-12/IL-18. TL1a synergized with IL-15 to enhance this response, while suppressing IL-15-induced IL-10 production. TL1a- and IL-15-mediated cytokine induction required the presence of IL-18, whereas induction of IL-5, IL-13, GM-CSF, and IL-22 was IL-12 independent. IL-18Rα(+)DR3(+)CD4(+) T cells with similar functionality were present in human skin, nasal polyps, and, in particular, the intestine, where in chronic inflammation they localized with IL-18-producing cells in lymphoid aggregates. Collectively, these results suggest that human memory IL-18Rα(+)DR3(+) CD4(+) T cells may contribute to antigen-independent innate responses at barrier surfaces.Mucosal Immunology advance online publication, 1 October 2014; doi:10.1038/mi.2014.87.Mucosal Immunology 10/2014; · 7.54 Impact Factor