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The tumor necrosis factor (TNF)-family cytokine TL1A (TNFSF15) costimulates T cells through its receptor DR3 (TNFRSF25) and is required for autoimmune pathology driven by diverse T-cell subsets. TL1A has been linked to human inflammatory bowel disease (IBD), but its pathogenic role is not known. We generated transgenic mice that constitutively express TL1A in T cells or dendritic cells. These mice spontaneously develop IL-13-dependent inflammatory small bowel pathology that strikingly resembles the intestinal response to nematode infections. These changes were dependent on the presence of a polyclonal T-cell receptor (TCR) repertoire, suggesting that they are driven by components in the intestinal flora. Forkhead box P3 (FoxP3)-positive regulatory T cells (Tregs) were present in increased numbers despite the fact that TL1A suppresses the generation of inducible Tregs. Finally, blocking TL1A-DR3 interactions abrogates 2,4,6 trinitrobenzenesulfonic acid (TNBS) colitis, indicating that these interactions influence other causes of intestinal inflammation as well. These results establish a novel link between TL1A and interleukin 13 (IL-13) responses that results in small intestinal inflammation, and also establish that TL1A-DR3 interactions are necessary and sufficient for T cell-dependent IBD.

SummaryDR3 (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.

DR3 is a TNF-receptor specifically expressed on lymphocytes which can costimulate lymphocyte activation. Its ligand, TL1A, can be produced by at least 3 different cell subsets: endothelial cells, lymphocytes and DC. TL1A and DR3 have been reported to be upregulated in biopsy samples and in animal models of IBD, providing circumstantial evidence of the involvement of this TNF ligand-receptor pair in IBD. We have generated TL1A transgenic mice that constitutively express TL1A by either T-cells or DC. Both of these transgenic lines develop spontaneous IBD. Constitutive expression of TL1A by T cells leads to a severe pathology found primarily in the ileum and duodenum in all founders, from an early age. Consistent with the role of TL1A as a T cell costimulator, the T cell population had an activated phenotype and increased effector subsets. Surprisingly, despite the inflammation, we observed increased FoxP3+ cells. Interestingly, IL-13 and to a lesser extent IL-17 are the cytokine mRNA that are the most elevated in the gut. In contrast, constitutive expression of TL1A by DC leads to a milder pathology that is more restricted to the ileum, and is detectable in older mice. Ectopic expression of TL1A appears to be able to overcome T-cell self-tolerance and drive IBD with no other overt stimuli. These findings suggest that TL1A may be an interesting target for therapy.