Group 1 CD1 in Infectious Disease and T Cell Development

第 1 组 CD1 在传染病和 T 细胞发育中的作用

• 批准号: 6828264
• 负责人: Chyung-Ru Wang
• 金额: $ 33.2万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-12-01 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6828264
• 关键词: CD1 molecule; Listeria; Mycobacterium tuberculosis; T cell receptor; T lymphocyte; cell differentiation; genetically modified animals; histogenesis; host organism interaction; immune response; laboratory mouse; leukocyte activation /transformation; lymphocyte proliferation; microorganism immunology; CD1 molecule; Listeria; Mycobacterium tuberculosis; T cell receptor; T lymphocyte; cell differentiation; genetically modified animals; histogenesis; host organism interaction; immune response; laboratory mouse; leukocyte activation /transformation; lymphocyte proliferation; microorganism immunology

DESCRIPTION (provided by applicant): The human CD1 locus encodes five nonpolymorphic MHC class I-like molecules. These proteins, designated CD1a, CD1b, CD1c, CD1d, and CD1e are divided into two groups based on sequence homology. Group 2 CD1, comprising human CD1d, is present in all mammalian species examined so far, where as group 1 CD1, comprising human CD1a, CD1b, CD1c, is absent in rodents. Several studies have clearly shown that group1 CD1 molecules can present lipid/glycolipid antigens derived from Mycobacteria to cytotoxic T cells, suggesting that group 1 CD1 may play an important role in immune resistance to mycobacterial infections. The high degree of conservation of CD1-restricted microbial antigens and the low degree of polymorphism of CD1, make CD1 molecules attractive targets for T- cell based vaccines against intracellular pathogens for a diverse population. However, the absence of a suitable animal model for group1 CD1 has limited the in vivo analysis of the contribution of CD1-restricted T cells to specific immunological challenges. To overcome this limitation, we have generated transgenic mice (hCD1Tg) that express human CD1a, CD1b, and CD1c in a pattern similar to that seen in human tissues. This proposal aims to use thehCD1 transgenic mouse as an animal model to study the role of group 1 CD1-restricted responses in the defense against intracellular microbial pathogens, e.g. Mycobacterium tuberculosis and Listeria monocytogenes. We will also assess the immunogenicity of known CD1-restricted mycobacterial lipid antigens in hCD1Tg mice. In addition to presenting microbial lipid antigens, group 1 CD1 molecules appear to directly activate many human CD1-restricted T cells in the absence of foreign antigens. It has been postulated that these group 1CD1-restricted autoreactive T cells may serve to elicit antigen-independent immunity at an early phase of microbial infection. We will generate transgenic mice which express an autoreactive TCR specific to group 1CD1 and introduce them onto the hCD1Tg background to study the requirements for the selection and maintenance of group 1 CD1-restricted T cells. The activation status and functional properties of these group 1 CD1-restricted auto reactive T cells will be examined following Mycobacteria infection to see if they are involved in the immune response. Collectively, these studies will lead to a better understanding of the in vivo function of group 1 CD1 in infectious disease and T cell development.

描述（由申请人提供）：人类CD1基因座编码五个非甲状化MHC类I类分子。这些蛋白质（指定的CD1A，CD1B，CD1C，CD1D和CD1E）基于序列同源性分为两组。迄今为止，所有检查的哺乳动物物种中都存在组成的第2组CD1，其中啮齿动物中没有人CD1的第1组CD1，包括人CD1A，CD1B，CD1C。几项研究清楚地表明，Group1 CD1分子可以提出脂质/糖脂抗原，这些脂质抗原从分枝杆菌衍生成细胞毒性T细胞，这表明第1组CD1可能在对分枝杆菌感染的免疫抗性中起重要作用。 CD1限制的微生物抗原的高度保存和CD1的低程度多态性，使CD1分子对基于T-细胞的疫苗具有吸引人的靶标针对各种种群的细胞内病原体。但是，缺乏用于组1 CD1的合适动物模型限制了对CD1限制的T细胞对特定免疫学挑战的贡献的体内分析。为了克服这一局限性，我们产生了转基因小鼠（HCD1TG），这些小鼠以类似于人类组织中的模式表达人CD1A，CD1B和CD1C。该建议旨在使用TheHCD1转基因小鼠作为动物模型，以研究1组CD1限制反应在防御细胞内微生物病原体中的作用，例如结核分枝杆菌和单核细胞增生李斯特菌。我们还将评估HCD1TG小鼠中已知的CD1限制性分枝杆菌脂质抗原的免疫原性。 除了呈现微生物脂质抗原外，第1组CD1分子似乎在没有异源抗原的情况下直接激活许多人类CD1限制的T细胞。据推测，这些1CD1限制的自动反应性T细胞可能在微生物感染的早期阶段引起抗原独立的免疫力。我们将生成转基因小鼠，该小鼠表达针对1CD1组的自动反应性TCR，并将其引入HCD1TG背景上，以研究选择和维持1组CD1限制的T细胞的要求。这些组1 CD1限制的自动反应性T细胞的激活状态和功能特性将在感染分枝杆菌后检查，以查看它们是否参与免疫反应。总的来说，这些研究将使对1组CD1在传染病和T细胞发育中的体内功能有更好的了解。