Group 1 CD1 in Infectious Disease and T Cell Development

描述（由申请人提供）：人CD 1基因座编码5种非多态性MHC I类样分子。这些蛋白质，命名为CD 1a、CD 1b、CD 1c、CD 1d和CD 1 e，根据序列同源性分为两组。包含人CD 1d的第2组CD 1存在于迄今为止检查的所有哺乳动物物种中，而包含人CD 1a、CD 1b、CD 1c的第1组CD 1在啮齿动物中不存在。一些研究已经清楚地表明，第1组CD 1分子可以将来自分枝杆菌的脂质/糖脂抗原呈递给细胞毒性T细胞，这表明第1组CD 1可能在分枝杆菌感染的免疫抵抗中发挥重要作用。CD 1限制性微生物抗原的高度保守性和CD 1的低多态性使得CD 1分子成为针对不同群体的细胞内病原体的基于T细胞的疫苗的有吸引力的靶。然而，缺乏一个合适的动物模型组1的CD 1限制了体内分析的贡献CD 1限制性T细胞特异性免疫挑战。为了克服这一限制，我们已经产生了转基因小鼠（hCD 1 Tg），表达人CD 1a，CD 1b，和CD 1c的模式类似于在人体组织中看到的。本研究旨在利用hCD 1转基因小鼠作为动物模型，研究第1组CD 1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生李斯特菌）中的作用。我们还将在hCD 1 Tg小鼠中评估已知的CD 1限制性分枝杆菌脂质抗原的免疫原性。 除了呈递微生物脂质抗原外，第1组CD 1分子似乎在不存在外源抗原的情况下直接激活许多人CD 1限制性T细胞。据推测，这些组1CD 1限制性自身反应性T细胞可能在微生物感染的早期阶段引起抗原非依赖性免疫。我们将产生转基因小鼠表达的自身反应性TCR特异性组1CD 1，并将它们引入到hCD 1 Tg的背景下，以研究选择和维持组1 CD 1限制性T细胞的要求。在分枝杆菌感染后，将检查这些第1组CD 1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应答。总的来说，这些研究将导致更好地了解1组CD 1在感染性疾病和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.