Regulation of Human IELs by CD94 and HLA-E

CD94 和 HLA-E 对人类 IEL 的调节

• 批准号: 6787648
• 负责人: BANA JABRI
• 金额: $ 26.69万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6787648
• 关键词: CD antigens; T cell receptor; T lymphocyte; antigen presenting cell; celiac disease; cell cell interaction; flow cytometry; gastrointestinal epithelium; gut associated lymphoid tissue; histocompatibility antigens; human tissue; immunoglobulin structure; inflammation; mucosal immunity; natural killer cells; receptor; receptor expression; tissue /cell culture

DESCRIPTION (Applicant's Abstract): In the microenvironment of the human gut epithelium, armed effector T cells (T-IELs) with cytolytic functions are tightly regulated by CD94/NKG2, a novel family of HLA-E specific heterodimeric receptors originally identified on NK cells. These receptors can switch adaptive responses on and off by using different activating or inhibitory NKG2 isotypes and appear to regulate remarkably large T-IEL clonal expansions in healthy individuals. In celiac disease, a condition associated with epithelial damage, they exclusively express activating isotypes, suggesting that dysregulation causes disease. The overarching goal of the proposed research is to develop a model of how adaptive immunity mediated by cytolytic effector T cells is regulated in the gut microenvironment by CD94/NKG2 receptors of innate immunity. The investigator will focus on three specific aims fundamental to understanding the biological significance of this regulatory system. In Specific Aim 1, expression and regulation of HLA-E and G on intestinal epithelial cells, cytokines produced in the GALT in normal and inflammatory conditions will be used to stimulate expression of HLA-E and G by freshly isolated IECs, IEC lines and professional APCs. In Specific Aim 2, expression and regulation of CD94/NKG2 isotypes by T-IELs, the investigator will characterize the pattern of expression of the different CD94/NKG2 isotypes, the TCR V-beta and V-alpha repertoire of T-IELs expressing distinct CD94/NKG2 isotypes (by spectroanalysis and sequencing), and the cytokine profile of T-IELs expressing distinct CD94/NKG2 isotypes. In Specific Aim 3, functional properties of CD94INKG2 receptors expressed by T-IELs, cloned T-IELs expressing single NKG2 isotypes will be used to determine how they contribute to cytolytic function and cytokine secretion and to characterize the biochemical signals involved. The proposed research will test in a molecularly well-defined system the general hypothesis that NK receptors and non-classical MHC class I-like molecules regulate interactions between T-IELs and intestinal epithelial cells. The results are likely to have important implications for our understanding of the processes that fine tune cytolytic T cell responses in the high antigen environment of the gut, regulating local immunity and controlling epithelial cell damage.

描述（申请人摘要）：在人类肠道的微环境中 上皮细胞中，具有溶细胞功能的武装效应 T 细胞 (T-IEL) 受 CD94/NKG2 严格调控，CD94/NKG2 是 HLA-E 特异性异二聚体的新家族 最初在 NK 细胞上发现的受体。这些受体可以转换 通过使用不同的激活或抑制 NKG2 来开启和关闭适应性反应 同种型，似乎可以调节 T-IEL 克隆扩增 健康的个体。在乳糜泻中，一种与上皮细胞相关的疾病 损伤，它们专门表达激活同种型，表明 失调会导致疾病。拟议研究的总体目标是 开发细胞溶解效应 T 如何介导适应性免疫的模型 细胞在肠道微环境中受到先天性 CD94/NKG2 受体的调节 免疫。研究人员将重点关注三个具体目标 了解该调节系统的生物学意义。在 具体目的1、HLA-E和G在肠道的表达及调控 正常和炎症状态下 GALT 中的上皮细胞、细胞因子 新鲜条件将用于刺激 HLA-E 和 G 的表达 隔离 IEC、IEC 线路和专业 APC。在具体目标 2 中，表达 以及 T-IEL 对 CD94/NKG2 同种型的调节，研究者将 表征不同 CD94/NKG2 同种型的表达模式， 表达不同 CD94/NKG2 的 T-IEL 的 TCR V-beta 和 V-alpha 库 同种型（通过光谱分析和测序），以及细胞因子谱 T-IEL 表达不同的 CD94/NKG2 同种型。在具体目标 3 中，功能性 T-IEL 表达的 CD94INKG2 受体的特性，克隆的 T-IEL 表达 单一 NKG2 同种型将用于确定它们如何促进细胞溶解 功能和细胞因子分泌并表征生化信号 涉及。拟议的研究将在分子明确的系统中进行测试 一般假设 NK 受体和非经典 MHC I 类样 分子调节 T-IEL 和肠上皮细胞之间的相互作用。 结果可能对我们的理解产生重要影响 微调高抗原中溶细胞 T 细胞反应的过程 肠道环境，调节局部免疫，控制上皮细胞 细胞损伤。