IEL and NKG2 Receptors in Celiac Disease

描述（由申请人提供）：乳糜泻是一种常见的炎症性肠道疾病，由饮食中的麸质诱导的遗传易感个体。虽然HLA-DQ 2或DQ 8限制性麦胶蛋白特异性CD 4 T细胞的存在是肠道固有层中疾病的重要组成部分，但集中观察表明，肠道内衬上皮的应激导致诱导MHC 1类配体，其进而扩增并激活具有细胞溶解活性的上皮内淋巴细胞（IEL）。活化的IEL不仅有助于上皮的破坏，而且它们经历转化成淋巴瘤，其频率增加。该建议将在细胞和分子水平上探索患病的腹腔上皮和lEL之间的相互作用。具体地，研究将集中于HLA-E和MIC的上皮诱导及其与由IEL表达的其同源NKG 2受体的相互作用。具体目标1将使用光谱分析和测序对疾病不同阶段和正常对照中IEL T细胞受体库的克隆组成进行高分辨率分析。具体目标2将确定对NKG 2受体的表达和功能的调节，所述NKG 2受体识别腹腔IEL上的HLA-E和MIC。具体目标3将进一步剖析腹腔IEL中NKG 2受体信号传导的分子和生物化学基础。具体目标4将在体内和器官培养中研究腹腔肠上皮细胞的HLA-E和MIC的表达以及麦胶蛋白和应激对它们的诱导。 总的来说，这些研究将剖析通过连接先天性免疫和适应性免疫的新型配体/受体系统在患病肠上皮中对人效应CTL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.