SELECTION OF INTESTINAL INTRAEPITHELIAL T CELLS

肠上皮内 T 细胞的选择

• 批准号: 6381231
• 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/6381231
• 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）是一种重要的免疫细胞。 肠上皮层的组成部分。 虽然他们有一个 与其他T细胞群体相比， 这些细胞的功能，以及在这些细胞中发现的大量T细胞， 上皮下固有层组织，是未知的。 已经提出 这些T淋巴细胞可以在特定的效应器中发挥作用， 对病原体的反应，维持上皮层，或 在诱导口服耐受性方面。 有证据表明， 这些T细胞的某些亚群通过胸腺外途径分化 可能位于肠道的中心。 在本申请中提出的研究旨在阐明一些 这些独特的肠道的发展和选择方面， 小鼠中的淋巴细胞群，重点关注TCR α β + 人口，这是人类的主要人口。 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工程的强大工具 缺陷小鼠来达到她的目标。 她将研究 MHC分子在IEL和LPL选择中的作用。 她会试图 识别参与发展的MHC I类分子， TAP1缺陷小鼠中存在TCR α β + CD8+ IEL。 她打算 以确定是否选择胸腺外IEL和LPL， 肠，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。 使用定义明确的TCR 转基因小鼠模型，她将确定T细胞的表型 由胸腺外途径选择。此外，她将确定， IEL和LPL可能会受到真正的选择过程， 取决于TCR的亲合力。 这种TCR转基因系统也将使 她也研究了IEL可能的负选择。 总之，所提出的实验旨在提供见解 肠道T细胞的发育途径。这些知识 将是理解这一生理重要性的关键 不同的T细胞群 由于肠道T细胞可能在 控制肠道炎症和预防炎症性肠病 疾病，在诱导口服耐受性，并在监测 癌上皮细胞，这些研究的结果可能是 对理解正常的 内环境稳定和肠粘膜的病理状况。