The TNF-family cytokine TL1A drives IL-13-dependent small intestinal inflammation

The 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 TCR repertoire, suggesting that they are driven by components in the intestinal flora. FoxP3(+) Treg were present in increased numbers despite the fact that TL1A suppresses the generation of inducible Treg. Finally, blocking TL1A-DR3 interactions abrogates TNBS-colitis, indicating that these interactions influence other causes of intestinal inflammation as well. These results establish a novel link between TL1A and IL-13 responses that results in small intestinal inflammation and establish that TL1A-DR3 interactions are necessary and sufficient for T cell-dependent IBD.