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

 描述(申请人提供)：人类，而不是鼠类啮齿动物表达第一组CD1分子，CD1a，b和c。有趣的是，第一组CD1分子与抗分枝杆菌免疫密切相关，因为它们可以呈递各种分枝杆菌衍生的脂类抗原，并且在感染结核分枝杆菌(Mtb)的个体中，第一组CD1特异性T细胞反应的频率较高。然而，由于缺乏小动物模型，没有直接证据表明第1组CD1限制性T细胞的保护能力。因此，我的实验室建立了一个转基因小鼠模型(HCD1Tg)，该模型含有人类第1组CD1基因，并支持第1组CD1限制性T细胞的发育。结核分枝杆菌感染hCD1Tg小鼠产生第1组CD1限制性结核分枝杆菌脂类抗原特异性T细胞反应。此外，过继转移第1组CD1限制性T细胞可保护机体免受感染。综上所述，这些数据表明，第1组CD1限制性T细胞在结核分枝杆菌获得性免疫中发挥作用，并可作为疫苗靶点。本研究旨在进一步阐明第1组CD1限制性T细胞在结核分枝杆菌感染不同阶段中的作用，并评价第1组CD1限制性T细胞是否在抵抗其他细菌病原体的免疫中发挥作用。在目标1中，我们将评估在二次结核分枝杆菌感染中是否可以产生记忆第1组CD1限制性T细胞，并确定与诱导记忆第1组CD1限制性T细胞相关的分子和细胞事件。虽然第1组CD1限制性结核分枝杆菌脂抗原特异性T细胞存在于结核分枝杆菌感染的早期阶段， 自身反应组1 CD1限制性T细胞在感染小鼠的肺中后期扩张。在目标2中，我们将评估这些T细胞的表面表型和功能特性，并确定它们在结核分枝杆菌感染过程中是否起到保护作用。此外，我们还将比较自身反应性T细胞和结核分枝杆菌脂类特异性第1组CD1限制性T细胞在结核分枝杆菌感染过程中的激活需求。到目前为止发现的第一组CD1限制性微生物脂类抗原主要是分枝杆菌来源的。关于第1组CD1限制性T细胞在抵抗其他细菌病原体的免疫中所起的作用，人们知之甚少。我们选择金黄色葡萄球菌(SA)是因为它是与医院感染相关的最常见的分离病原体之一，并且SA含有几种与CD1结合抗原有共同特征的脂类。在目标3中，我们建议评估系统性金黄色葡萄球菌感染背景下第1组CD1限制性T细胞的动力学、扩增和功能，并确定刺激性金黄色葡萄球菌脂类抗原的结构。总而言之，这些研究将有助于更好地理解第1组CD1限制性T细胞如何有助于对结核分枝杆菌和金黄色葡萄球菌的保护性免疫，以及它们是否可以作为开发基于脂类抗原的疫苗的靶点。

 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.