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

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+ 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 WT mice. Furthermore, the frequency of IFN-?+ 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 WT CD4+-cell recipients. These data establish for the first time a role for DR3 in a host defence responce

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

TNFRSF25 is a member of the TNF receptor superfamily (TNFRSF) that binds to the TNF-like protein TL1A. Although recent studies have demonstrated a role for TNFRSF25 in regulating CD4+ T-cell responses, it remains to be determined if TNFRSF25 functions as a costimulatory receptor for CD8+ T cells. Here, we demonstrate that ectopic expression of TL1A on mouse plasmacytomas promotes elimination of tumor cells in a CD8+ T-cell-dependent manner and renders mice immune to a subsequent challenge with tumor cells. To gain further insight into the role of TNFRSF25 in CD8+ 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+ T cells as well as their differentiation into CTLs. Furthermore, we show that TNFRSF25 also functions as a costimulatory receptor for memory CD8+ T cells. Thus, TNFRSF25 triggering enhances the secondary expansion of endogenous antigen-specific memory CD8+ 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+ T cells

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

Rheumatoid arthritis (RA) is a chronic inflammatory disease of synovial joints that is associated with cartilage and bone destruction. Death Receptor 3 (DR3), a tumor necrosis factor (TNF) receptor superfamily member, has recently been associated with the pathogenesis of RA. We demonstrate that absence of DR3 confers resistance to the development of adverse bone pathology in experimental antigen-induced arthritis (AIA). DR3ko mice exhibited a reduction in all histopathological hallmarks of AIA but, in particular, failed to develop subchondral bone erosions and were completely protected from this characteristic of AIA. In contrast, TNF-like protein 1A (TL1A), the ligand for DR3, exacerbated disease in a dose- and DR3-dependent fashion. Analysis of osteoclast number within AIA joint revealed a reduction in areas susceptible to bone erosion in DR3ko mice, whereas in vitro osteoclastogenesis assays showed that TL1A could directly promote osteoclastogenesis in mouse and man. Treatment with antagonistic anti-TL1A mAb protected animals in a systemic model of RA disease collagen-induced arthritis. We therefore conclude that the DR3–TL1A pathway regulates joint destruction in two murine models of arthritis and represents a potential novel target for therapeutic intervention in inflammatory joint diseas