The TNF-Family Receptor DR3 is Essential for Diverse T Cell-Mediated Inflammatory Diseases

Abstract

DR3 (TRAMP, LARD, WSL-1, TNFRSF25) is a death-domain-containing tumor necrosis factor (TNF)-family receptor primarily expressed on T cells. TL1A, the TNF-family ligand for DR3, can costimulate T cells, but the physiological function of TL1A-DR3 interactions in immune responses is not known. Using DR3-deficient mice, we identified DR3 as the receptor responsible for TL1A-induced T cell costimulation and dendritic cells as the likely source for TL1A during T cell activation. Despite its role in costimulation, DR3 was not required for in vivo T cell priming, for polarization into T helper 1 (Th1), Th2, or Th17 effector cell subtypes, or for effective control of infection with Toxoplasma gondii. Instead, DR3 expression was required on T cells for immunopathology, local T cell accumulation, and cytokine production in Experimental Autoimmune Encephalomyelitis (EAE) and allergic lung inflammation, disease models that depend on distinct effector T cell subsets. DR3 could be an attractive therapeutic target for T cell-mediated autoimmune and allergic diseases.

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

“…Consistent with these findings transgenic mice that constitutively express TL1A have increased levels of IL-13 and IL-17 but not IFN-g under steady-state conditions [15,16]. However, other studies have shown that addition of TL1A or agonist anti-DR3 mAb enhances the production of both IL-4 and IFN-g during in vitro activation of naïve CD4 1 T cells [5,14]. To decipher the role of DR3 in host immunity to infection, we have examined the immune response against Salmonella enterica serovar Typhimurium in DR3-deficient mice.…”

“…Infection with S. enterica Typhimurium induces expression of TL1A in macrophages TL1A expression is transiently increased in macrophages and dendritic cells by diverse stimuli, including LPS and immune complexes [5,12]. To determine whether TL1A is upregulated during infection, mice were challenged with S. enterica Typhimurium and TL1A mRNA expression measured in the spleen by quantitative RT-PCR (Fig.…”

“…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].…”

“…Studies using TL1A À/À or DR3 À/À mice have revealed a role for TL1A/DR3 in exacerbating Th2-and Th17-cell-dependent inflammatory and autoimmune conditions [5,13]. In contrast, no studies have reported a role for DR3 in host immune responses to infection.…”

“…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].Studies using TL1A À/À or DR3 À/À mice have revealed a role for TL1A/DR3 in exacerbating Th2-and Th17-cell-dependent inflammatory and autoimmune conditions [5,13]. In contrast, no studies have reported a role for DR3 in host immune responses to infection.…”