B220+DN Tcells in Mucosal Tolerance and Inflammation

描述（由申请人提供）：溃疡性结肠炎和克罗恩病，统称为炎症性肠病（IBD），是慢性自发复发的胃肠道疾病。IBD至少部分是由自身免疫机制介导的，但目前尚不完全清楚。对明确定义的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，参与调节粘膜耐受。然而，这些调节细胞都不存在于胃肠道中。我们发现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，并在疾病的scid转移模型中预防T细胞介导的结肠炎。其抑制机制包括抑制IL-2转录和抑制CD25上调。这些发现是通过分析在缺乏Fas或FasL基因的小鼠中积累的B220+ DN T细胞获得的。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，但其功能尚未明确。本文提出了三个特定的目的，以了解DN T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+ DN T细胞在调节粘膜耐受中的潜在作用。三个特定目的是：1)表征B220+ DN T细胞抑制结肠炎的细胞机制2)确定Fas通路在控制调节性T细胞功能中的作用3)表征上皮内（iel）和肝脏B220+ DN T细胞的功能。这些研究可能为结肠和肝脏的免疫反应是如何调节和维持黏液耐受性提供新的见解。此外，它们为健康个体和IBD患者的B220+ DN T细胞分析奠定了基础。

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.