Immunoregulation Section, Autoimmunity Branch, NIAMS, Bethesda, Maryland, USA.
Mucosal Immunol. 2011 Mar;4(2):172-85. doi: 10.1038/mi.2010.67. Epub 2010 Oct 27.
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.
肿瘤坏死因子（TNF）家族细胞因子 TL1A（TNFSF15）通过其受体 DR3（TNFRSF25）共刺激 T 细胞，是多种 T 细胞亚群驱动的自身免疫病理所必需的。TL1A 与人类炎症性肠病（IBD）有关，但它的致病作用尚不清楚。我们生成了在 T 细胞或树突状细胞中组成性表达 TL1A 的转基因小鼠。这些小鼠自发地发展出依赖于 IL-13 的炎症性小肠病理，这与线虫感染引起的肠道反应非常相似。这些变化依赖于多克隆 T 细胞受体（TCR）库的存在，表明它们是由肠道菌群中的成分驱动的。尽管 TL1A 抑制诱导性 Treg 的产生，但 FoxP3 阳性调节性 T 细胞（Treg）的数量仍增加。最后，阻断 TL1A-DR3 相互作用可消除 2,4,6 三硝基苯磺酸（TNBS）结肠炎，表明这些相互作用也影响其他肠道炎症的原因。这些结果在 TL1A 和白细胞介素 13（IL-13）反应之间建立了一个新的联系，导致小肠炎症，并证实 TL1A-DR3 相互作用是 T 细胞依赖性 IBD 所必需和充分的。
