B220+DN Tcells in Mucosal Tolerance and Inflammation

描述(申请人提供)：溃疡性结肠炎和克罗恩病，统称为炎症性肠病(IBD)，是一种慢性自发性复发性胃肠道疾病。IBD至少在一定程度上是由尚未完全了解的自身免疫机制介导的。对明确的IBD动物模型的研究表明，几种类型的调节性T细胞，包括CD4+CD25+T细胞、TR1和Th3细胞，参与了粘膜耐受的调节。然而，这些调节细胞中没有一个是自然存在于胃肠道的。我们已经确认B220+dN T细胞是一种新型的调节性T细胞，在体外抑制多克隆T细胞的激活，并在SCID转移模型中预防T细胞介导的结肠炎。其作用机制包括抑制IL-2转录和抑制CD25上调。这些发现是通过对Fas或FasL基因缺陷小鼠体内积累的B220+dN T细胞的分析得出的。然而，表型相似的B220+dN T细胞大量存在于阑尾、结肠、盲肠和肝脏的上皮内部位，但它们的功能尚未确定。我们提出了三个特定的目标，以了解DNT细胞介导的抑制的细胞机制，以及位于大肠和肝脏上皮内部位的B220+DNT细胞在调节粘膜耐受性中的潜在作用。三个具体目标是：1)研究B220+DN T细胞抑制结肠炎的细胞机制；2)确定Fas通路在调节T细胞功能中的作用；3)研究B220+DNT细胞和B220+DNT细胞的功能。这些研究可能为如何调节结肠和肝脏的免疫反应以及维持粘膜耐受提供新的见解。此外，它们还为分析健康人和IBD患者的B220+dN T细胞奠定了基础。

DESCRIPTION (provided by applicant): Ulcerative colitis and Crohn's' disease, collectively referred to as Inflammatory Bowel disease (IBD), are chronic spontaneously relapsing disorders of the gastrointestinal tract. IBD is mediated at least in part by autoimmune mechanisms that are not completely understood. Studies of well-defined animal models of IBD have implicated several types of regulatory T cells, including CD4+CD25+ T cells, Tr1 and Th3 cells, in regulation of mucosal tolerance. However, none of these regulatory cells is known to naturally reside in the gastrointestinal tract. We have identified B220+ DN T cells as a new type of regulatory T cells that suppress polyclonal T cell activation in vitro and prevent T cell-mediated colitis in the SCID-transfer model of the disease. The mechanism of suppression involves inhibition of IL-2 transcription and inhibition of CD25 upregulation. These findings were obtained by analysis of B220+ DN T cells that accumulate in mice deficient in Fas or FasL genes. However, phenotypically similar B220+DN T cells exist in significant numbers at intraepithelial sites of the appendix, colon, cecum and in the liver, but their function has not been defined. Three Specific Aims are proposed to understand the cellular mechanisms of DN T cell-mediated suppression and the potential role of B220+ DN T cells that reside at the intraepithelial sites of the large intestine and the liver in regulating mucosal tolerance. The three Specific Aims are: 1) Characterize the cellular mechanism by which B220+ DN T cells suppress colitis 2) Define the role of the Fas pathway in controlling regulatory T cell function 3) Characterize the function of intraepithelial (IELs) and hepatic B220+ DN T cells. These studies may provide novel insights into how immune responses of the colon and liver are regulated and mucosol tolerance is maintained. In addition, they lay the groundwork for the analysis of B220+ DN T cell in healthy individuals and IBD patients.