SELECTION OF INTESTINAL INTRAEPITHELIAL T CELLS

肠上皮内 T 细胞的选择

• 批准号: 6523728
• 负责人: HILDE MC CHEROUTRE
• 金额: $ 13.16万
• 依托单位: LA JOLLA INSTITUTE FOR IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-05 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6523728
• 关键词: CD1 molecule; CD4 molecule; CD8 molecule; MHC class I antigen; MHC class II antigen; T cell receptor; T lymphocyte; cell differentiation; cellular immunity; flow cytometry; gastrointestinal epithelium; genetically modified animals; laboratory mouse; leukopoiesis; mucosal immunity; polymerase chain reaction; thymus

Intestinal intraepithelial T lymphocytes (IEL) are a significant component of the epithelial layer of the intestine. While they have a unique phenotype and behavior when compared to other T-cell populations, the function of these cells, and the numerous T-cells found in the subepithelial lamina propria tissue, is not known. It has been proposed that these T lymphocytes could play a role in the specific effectors responses to pathogens, in the maintenance of the epithelial layer, or in the induction of oral tolerance. There is evidence, suggesting that some subsets of these T-cells differentiate via an extrathymic pathway that may be centered within the intestine. The studies proposed in this application are intended to elucidate some aspects of the development and selection of these unique intestinal lymphocyte population in the mouse, focusing upon the TCR alpha beta+ population, which is the predominant population in humans. As IEL and LPL are difficult to expand and culture in vitro, the investigator will take full advantage of the powerful tools of transgenic and gene deficient mice to reach her goals. She will study the requirement for MHC molecules in the selection of IEL and LPL. She will attempt to identify the MHC class I molecules involved in the development of the TCR alpha beta+ CD8+ IEL present in TAP1 deficient mice. She intends to determine if extrathymic IEL and LPL are selected within the intestine, by analyzing transgenic mice in which class I or class II molecule expression is confined to this tissue. Using well defined TCR transgenic mouse models, she will identify the phenotype of T-cells selected by the extrathymic pathway. Furthermore, she will determine if IEL and LPL are likely to be subject to a true selection process that depends upon TCR avidity. This TCR transgenic system also will enable her to study the possible negative selection of IEL as well. In summary, the proposed experiments are intended to provide insight into the developmental pathway of intestinal T-cells. This knowledge will be crucial in understanding the physiologic importance of this distinct T-cell population. As intestinal T-cells have possible roles in controlling intestinal inflammation and preventing inflammatory bowel disease, in the induction of oral tolerance, and in the surveillance for cancerous epithelial cells, the results from these studies are likely to have important ramifications for understanding both normal homeostasis and pathological conditions of the intestinal mucosa.

肠上皮内 T 淋巴细胞 (IEL) 是重要的 肠上皮层的组成部分。 虽然他们有一个 与其他 T 细胞群相比，具有独特的表型和行为， 这些细胞的功能，以及体内发现的大量 T 细胞 上皮下固有层组织，尚不清楚。 已提出 这些T淋巴细胞可以在特定效应器中发挥作用 对病原体的反应，维持上皮层，或 诱导口服耐受。 有证据表明 这些 T 细胞的一些亚群通过胸腺外途径分化 它可能位于肠道的中心。 本申请中提出的研究旨在阐明一些 这些独特的肠道的开发和选择方面 小鼠淋巴细胞群，重点关注 TCR αβ+ 人口，即人类中的主要人口。 作为 IEL 和 LPL难以在体外扩增和培养，研究者将 充分利用转基因和基因的强大工具 有缺陷的老鼠无法实现她的目标。 她将研究以下要求： IEL和LPL中MHC分子的选择。 她将尝试 鉴定参与发育的 MHC I 类分子 TCR alpha beta+ CD8+ IEL 存在于 TAP1 缺陷小鼠中。 她打算 以确定是否在范围内选择了胸外 IEL 和 LPL 肠道，通过分析转基因小鼠，其中 I 类或 II 类 分子表达仅限于该组织。 使用明确的 TCR 转基因小鼠模型，她将识别 T 细胞的表型 由胸腺外途径选择。此外，她将确定是否 IEL 和 LPL 可能会经过真正的选拔过程， depends upon TCR avidity. This TCR transgenic system also will enable her to study the possible negative selection of IEL as well. 总之，所提出的实验旨在提供见解 进入肠道T细胞的发育途径。这些知识 will be crucial in understanding the physiologic importance of this distinct T-cell population. As intestinal T-cells have possible roles 控制肠道炎症并预防炎症性肠病 疾病、诱导口服耐受以及监测 癌性上皮细胞，这些研究的结果很可能 to have important ramifications for understanding both normal 肠粘膜的稳态和病理状况。