IEL and NKG2 Receptors in Celiac Disease

描述（由申请人提供）：乳糜泻是一种在遗传易感个体中由膳食麸质引起的常见炎症性肠道疾病。虽然HLA-DQ2或dq8限制性麦溶蛋白特异性CD4 T细胞的存在是肠道固有层疾病的重要组成部分，但趋同的观察表明，肠道上皮的应激导致MHC 1类配体的诱导，从而扩大和激活具有细胞溶解活性的上皮内淋巴细胞（IEL）。激活的水平不仅有助于上皮的破坏，但他们经历转化为淋巴瘤的频率增加。本研究将从细胞和分子水平探讨患病乳糜泻上皮与上皮细胞之间的相互作用。具体来说，研究将集中在HLA-E和MIC的上皮诱导以及它们与同源的NKG2受体的相互作用上。特异性目标1将使用光谱分型和测序对疾病不同阶段和正常对照的IEL T细胞受体库的克隆组成进行高分辨率分析。特异性目的2将确定识别HLA-E和MIC的NKG2受体在乳糜泻水平上的表达和功能调控。特异性目的3将进一步剖析腹腔水平NKG2受体信号转导的分子和生化基础。特异性目的4将在体内和器官培养中研究HLA-E和MIC在腹腔上皮细胞中的表达以及麦胶蛋白和应激对它们的诱导作用。

DESCRIPTION (provided by applicant): Celiac disease is a common inflammatory intestinal disease induced by dietary gluten in genetically predisposed individuals. While the presence of HLA-DQ2 or DQ8-restricted gliadin-specific CD4 T cells is an essential component of the disease in the gut lamina propria, convergent observations indicate that stress of the epithelium lining the gut leads to the induction of MHC class-1 like ligands which in turn expand and activate intraepithelial lymphocytes (IEL) with cytolytic activity. Activated lELs not only contribute to the destruction of the epithelium, but they undergo transformation into lymphomas whh increased frequency. This proposal will explore at the cellular and molecular level the interactions between the diseased celiac epithelium and lELs. Specifically, studies will focus on the epithelial induction of HLA-E and MIC and their interaction with their cognate NKG2 receptors expressed by lELs. Specific aim 1 will use spectratyping and sequencing to perform high resolution analysis of the clonal composition of the IEL T cell receptor repertoire at different stages of the disease and in normal controls. Specific aim 2 will determine the regulation of expression and function of the NKG2 receptors that recognize HLA-E and MIC on celiac lELs. Specific aim 3 will further dissect the molecular and biochemical basis of NKG2 receptor signaling in celiac lELs. Specific aim 4 will study the expression of HLA-E and MIC by celiac intestinal epithelial cells and their induction by gliadin and stress in vivo and in organ culture. Collectively, these studies will dissect the fine regulation of human effector CTLs in a diseased intestinal epithelium by a novel ligand/receptor system linking innate and adaptive immunity.