IEL and NKG2 Receptors in Celiac Disease

描述(申请人提供)：乳糜泻是一种常见的炎症性肠道疾病，由饮食面筋引起的遗传倾向的个人。虽然HLADQ2或DQ8限制性的醇溶蛋白特异性CD4T细胞的存在是肠道固有层疾病的重要组成部分，但收敛观察表明，肠道衬里上皮的应激导致MHC-1类配体的诱导，这反过来又扩大并激活具有细胞溶解活性的上皮内淋巴细胞(IEL)。激活的LEL不仅有助于破坏上皮，而且随着频率的增加，它们会转化为淋巴瘤。这项建议将在细胞和分子水平上探索病变的腹膜上皮和LELs之间的相互作用。具体地说，研究将集中在上皮细胞对人类白细胞抗原E和MIC的诱导以及它们与LELs表达的同源NKG2受体的相互作用。具体目标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细胞受体谱系的克隆组成进行高分辨率分析。特异性目标2将确定识别HLAE和MIC的NKG2受体的表达和功能的调节。具体目标3将进一步剖析NKG2受体信号转导的分子和生化基础。目的4研究在体内和器官培养条件下，HLAE和MIC的表达以及醇溶蛋白和应激对其的诱导作用。 总之，这些研究将剖析人类效应CTL通过一种新的连接天然免疫和获得性免疫的配体/受体系统在患病的肠道上皮细胞中的精细调节。

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.