The Role of Group 1 CD1-restricted T Cells in Infectious Disease

 描述（由申请方提供）：人类表达第1组CD 1分子，即CD 1a、B和c，但不表达鼠类。有趣的是，第1组CD 1分子与抗分枝杆菌免疫密切相关，因为它们可以呈递多种分枝杆菌衍生的脂质抗原，并且在结核分枝杆菌（Mtb）感染个体中以较高频率检测到第1组CD 1特异性T细胞应答。然而，由于缺乏小动物模型，没有直接证据表明第1组CD 1限制性T细胞的保护能力。因此，我的实验室产生了一种转基因小鼠模型（hCD 1 Tg），该模型含有人类1组CD 1基因座，并支持1组CD 1限制性T细胞的发育。用Mtb感染hCD 1 Tg小鼠产生第1组CD 1限制性Mtb脂质抗原特异性T细胞应答。此外，过继转移组1的CD 1-限制性T细胞赋予保护免受感染。总之，这些数据表明，第1组CD 1限制性T细胞在对结核分枝杆菌的适应性免疫中发挥作用，并可作为疫苗靶点。该提案旨在进一步阐明第1组CD 1限制性T细胞在结核分枝杆菌感染的不同阶段中的作用，并评估第1组CD 1限制性T细胞是否在针对其他细菌病原体的免疫中发挥作用。在目标1中，我们将评估记忆组1 CD 1限制性T细胞是否可以在继发性结核分枝杆菌感染中产生，并确定与记忆组1 CD 1限制性T细胞诱导相关的分子和细胞事件。虽然第1组CD 1限制性Mtb脂质抗原特异性T细胞存在于Mtb感染的早期阶段， 自身反应性组1 CD 1限制性T细胞在感染小鼠的肺中在后期阶段扩增。在目标2中，我们将评估这些T细胞的表面表型，功能特性，并确定它们是否在Mtb感染期间发挥保护作用。此外，我们将比较自身反应性和结核分枝杆菌脂质特异性第1组CD 1限制性T细胞在结核分枝杆菌感染过程中的活化要求。到目前为止鉴定的第1组CD 1限制性微生物脂质抗原主要是分枝杆菌来源的。关于第1组CD 1限制性T细胞在对其他细菌病原体的免疫中所起的作用，人们知之甚少。我们选择了金黄色葡萄球菌（SA），因为它是最常见的医院感染相关的病原体之一，SA含有几种脂质，与CD 1结合抗原共有的特征。在目标3中，我们建议在系统性SA感染的背景下评估第1组CD 1限制性T细胞的动力学、扩增和功能，并确定刺激性SA脂质抗原的结构。总的来说，这些研究将有助于更好地了解第1组CD 1限制性T细胞如何有助于对Mtb和SA的保护性免疫，以及它们是否可以成为开发基于脂质抗原的疫苗的目标。

 DESCRIPTION (provided by applicant): Humans but not muroid rodents express group 1 CD1 molecules, CD1a, b, and c. Interestingly, group 1 CD1 molecules are closely tied to anti-mycobacterial immunity because they can present a variety of mycobacteria-derived lipid antigens and group 1 CD1-specific T cell responses are detected at higher frequencies in Mycobacterium tuberculosis (Mtb) infected individuals. However, due to the lack of a small animal model, there is no direct evidence of the protective capacity of group 1 CD1-restricted T cells. Therefore, my lab generated a transgenic mouse model (hCD1Tg) that harbored the human group 1 CD1 locus and supported the development of group 1 CD1-restricted T cells. Infection of hCD1Tg mice with Mtb generated group 1 CD1-restricted Mtb lipid antigen-specific T cell responses. In addition, adoptive transfer of group 1 CD1-restricted T cells conferred protection against infection. Taken together, these data indicate that group 1 CD1-restricted T cells play a role in adaptive immunity to Mtb and could serve as vaccine targets. This proposal seeks to further elucidate the role of group 1 CD1-restricted T cells in different stages of Mtb infection and evaluate whether group 1 CD1-restricted T cells play a role in immunity against other bacterial pathogens. In aim 1, we will evaluate whether memory group 1 CD1-restricted T cells can be generated in secondary Mtb infection and determine the molecular and cellular events associated with the induction of memory group 1 CD1-restricted T cells. While group 1 CD1-restricted Mtb lipid antigen-specific T cells are present during early stages of Mtb infection, autoreactive group 1 CD1-restricted T cells expand at later stages in the lung of infected mice. In aim 2, we will evaluate the surface phenotype, functional properties of these T cells and determine whether they play a protective role during Mtb infection. In addition, we will compare the activation requirements of autoreactive and Mtb lipid-specific group 1 CD1- restricted T cells during Mtb infection. The group 1 CD1-restricted microbial lipid antigens identified thus far are mainly of mycobacterial origin. There is relatively little known about the role group 1 CD1-restricted T cells play in immunity against other bacterial pathogens. We have selected Staphylococcus aureus (SA) because it is one of the most frequently isolated pathogens associated with nosocomial infections and SA contains several lipids that share common features with CD1-binding antigens. In aim 3, we propose to assess the kinetics, expansion, and function of group 1 CD1-restricted T cells in the context of a systemic SA infection and identify the structure of stimulatory SA lipid antigens. Collectively, these studies will lead to a better understanding of how group 1 CD1-restricted T cells contribute to protective immunity against Mtb and SA and whether they can be targeted for the development of lipid antigen-based vaccines.