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

Abstract

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,...

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

“…The TNF family cytokine TL1A costimulates T cells and innate lymphocytes through its unique receptor DR3 ( Tnfrsf25 ). TL1A is synthesized in response to TLR ligands and other proinflammatory stimuli and optimizes T cell responses to bacterial pathogens such as salmonella and viral infections (1, 2). TL1A may also be involved in autoimmune disease pathogenesis, as TL1A levels are elevated in chronic inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease (3-5).…”

A Novel Role for TL1A/DR3 in Protection against Intestinal Injury and Infection

“…demonstrating deficient bacterial clearance and fewer Th1 cells in DR3 deficient mice challenged by i.p. infection with Salmonella (44). However, to our knowledge, our study is the first to demonstrate a role for DR3 in protection against oral Salmonella infection, which is the physiological route of infection for this agent.…”

Membrane Trafficking of Death Receptors: Implications on Signalling

“…TL1A enhances, like other members of the TNF family, T-cell proliferation and cytokine production. Additionally, TL1A-DR3 interactions exhibit prominent effects on T-cell polarization, T-cell homeostasis and T-cell-mediated immune response against bacteria and viruses [135]. For further information the reader is referred to [136].…”