Group 1 CD1 in Infectious Disease and T Cell Development

描述(申请人提供)：人类CD1基因座编码5个非多态的MHC类I类分子。根据序列同源性，这些蛋白分别命名为CD1a、CD1b、CD1c、CD1d和CD1e。包括人CD1d在内的第2组CD1在所有被研究的哺乳动物中都存在，而在啮齿类动物中不存在由人CD1a、CD1b和CD1c组成的第1组CD1。多项研究表明，第1组CD1分子可将分枝杆菌来源的脂类/糖脂抗原递呈给细胞毒性T细胞，提示第1组CD1可能在分枝杆菌感染的免疫抵抗中发挥重要作用。CD1限制性微生物抗原的高度保守性和CD1的低多态性使CD1分子成为针对不同人群的T细胞疫苗的靶点。然而，对于CD1组CD1缺乏合适的动物模型，限制了体内分析CD1限制性T细胞对特定免疫挑战的贡献。为了克服这一限制，我们培育了转基因小鼠(HCD1Tg)，它们以类似于人类组织中看到的模式表达人CD1a、CD1b和CD1c。本研究旨在利用hCD1转基因小鼠作为动物模型，研究第一组CD1限制性反应在防御细胞内微生物病原体如结核分枝杆菌和单核细胞增多性李斯特菌中的作用。我们还将评估已知的CD1限制性分枝杆菌脂类抗原在hCD1Tg小鼠中的免疫原性。 除了呈递微生物脂类抗原外，第1组CD1分子似乎在没有外来抗原的情况下直接激活许多人类CD1限制性T细胞。据推测，这些1CD1组限制性自身反应性T细胞可能在微生物感染的早期阶段起到诱导抗原非依赖性免疫的作用。我们将建立表达1CD1组特异性自身反应性TCR的转基因小鼠，并将它们引入hCD1Tg背景，以研究1CD1限制性T细胞的选择和维持的要求。在分枝杆菌感染后，将检查这些第1组CD1限制性自身反应性T细胞的激活状态和功能特性，以确定它们是否参与免疫反应。总之，这些研究将有助于更好地理解第1组CD1在感染疾病和T细胞发育中的体内功能。

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.