Group 1 CD1 in Infectious Disease and T Cell Development

描述（由申请人提供）：人类CD1基因座编码五种非多态性MHC I类样分子。这些蛋白质被命名为 CD1a、CD1b、CD1c、CD1d 和 CD1e，根据序列同源性分为两组。第2组CD1，包括人CD1d，存在于迄今为止检查的所有哺乳动物物种中，而第1组CD1，包括人CD1a、CD1b、CD1c，在啮齿类动物中不存在。多项研究清楚地表明，1 组 CD1 分子可以将源自分枝杆菌的脂质/糖脂抗原呈递给细胞毒性 T 细胞，这表明 1 组 CD1 可能在对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 的低度多态性，使得 CD1 分子成为针对不同人群的针对细胞内病原体的基于 T 细胞的疫苗的有吸引力的目标。然而，由于缺乏适合 CD1 组 1 的动物模型，限制了 CD1 限制性 T 细胞对特定免疫挑战的贡献的体内分析。为了克服这一限制，我们培育了转基因小鼠 (hCD1Tg)，它们以与人体组织中相似的模式表达人类 CD1a、CD1b 和 CD1c。本提案旨在使用 hCD1 转基因小鼠作为动物模型，研究 1 组 CD1 限制性反应在防御细胞内微生物病原体（例如细菌）中的作用。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。 除了呈递微生物脂质抗原外，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 限制性自身反应性 T 细胞可能有助于在微生物感染的早期引发不依赖于抗原的免疫。我们将产生表达针对 1CD1 组的自身反应性 TCR 的转基因小鼠，并将它们引入 hCD1Tg 背景，以研究选择和维持 1 组 CD1 限制性 T 细胞的要求。这些 1 组 CD1 限制性自身反应性 T 细胞的激活状态和功能特性将在分枝杆菌感染后进行检查，以确定它们是否参与免疫反应。总的来说，这些研究将有助于更好地了解 1 组 CD1 在传染病和 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.