Group 1 CD1 in Infectious Disease and T Cell Development

第 1 组 CD1 在传染病和 T 细胞发育中的作用

• 批准号: 7994164
• 负责人: Chyung-Ru Wang
• 金额: $ 37.74万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-12-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7994164
• 关键词: Address; Adoptive Cell Transfers; Adoptive Transfer; Animal Model; Antigen-Presenting Cells; Antigens; Bacterial Infections; CD1 Antigens; Cause of Death; Cell Line; Cell Wall; Cell physiology; Cells; Communicable Diseases; Cytotoxic T-Lymphocytes; Data; Dendritic Cells; Development; Disease; Drug or chemical Tissue Distribution; Epitopes; Exhibits; Exposure to; Family; Frequencies; Human; Immune response; Immunity; Immunization; Individual; Infection; Kinetics; Lead; Lipids; Location; Measures; Mediating; Modeling; Mus; Mycobacterium Infections; Mycobacterium tuberculosis; Mycobacterium tuberculosis antigens; Mycolic Acid; Natural Immunity; Nature; Pattern; Phenotype; Play; Production; Property; Protocols documentation; Regulation; Relative (related person); Resistance; Role; Secondary Immunization; Study models; Subunit Vaccines; Surface; T cell response; T-Cell Development; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Transgenic Mice; Transgenic Model; Transgenic Organisms; Tuberculosis; Tuberculosis Vaccines; Vaccines; adaptive immunity; autoreactive T cell; autoreactivity; base; cytokine; efficacy testing; enzyme linked immunospot assay; immune resistance; immunogenicity; improved; in vivo; mouse model; mycobacterial; novel; novel vaccines; outcome forecast; protective efficacy; public health relevance; response; vaccination against tuberculosis; vaccine development

DESCRIPTION (provided by applicant): The human group 1 CD1 molecules CD1a, CD1b, and CD1c have been shown to present both endogenous and mycobacterial-derived lipid antigens to various subsets of T cells. Group 1 CD1- restricted immune responses have been implicated in anti-mycobacterial immunity; however, their role in infection is unknown due to the lack of a suitable animal model. We have generated transgenic mice (hCD1Tg) that express human group 1 CD1 molecules in a pattern similar to humans, and support the development of T cells that are restricted to group 1 CD1. Both infection with Mycobacterium tuberculosis (Mtb) and immunization with Mtb lipids elicit group 1 CD1-restricted Mtb- lipid antigen-specific T cell responses in hCD1Tg mice, and secondary immunization induces more rapid responses than primary immunization. In addition, group 1 CD1-restricted T cells generated from hCD1Tg mice can recognize mycobacterial antigens described in humans. Taken together, these data indicate that group 1 CD1-restricted T cells play a role in adaptive immunity and could serve as targets for Mtb vaccine development. This proposal seeks to study the in vivo function of group 1 CD1-restricted T cells during Mtb infection and to test the efficacy of a lipid-based vaccine for Mtb that targets group 1 CD1-restricted T cells using the hCD1Tg mouse model. In Aim 1, we propose to identify immunodominant Mtb antigens presented by group 1 CD1 in Mtb-infected hCD1Tg mice and evaluate the protective efficacy of these antigens in a lipid vaccine upon Mtb challenge. In Aim 2, we propose to generate retrogenic mice which express TCRs specific to distinct Mtb lipid antigens, and investigate the activation kinetics, effector function, and protective role of these T cells using an adoptive transfer approach. While group 1 CD1-restricted Mtb lipid antigen-specific T cells recognize foreign antigens directly, group 1 CD1-restricted autoreactive T cells may be activated during infection through recognition of endogenous antigen presented by TLR-matured antigen presenting cells and contribute to innate anti-mycobacterial responses, analogous to what has been described for group 2 CD1d-restricted NKT cells. In our third Aim, we will therefore investigate the developmental requirements and function of autoreactive group 1 CD1-restricted T cells during Mtb infection using a TCR transgenic model. Collectively, these studies will lead to a better understanding of how group 1 CD1-restricted T cells contribute to protective immunity against Mtb and whether they can be targeted for the development of lipid antigen-based Mtb vaccines. PUBLIC HEALTH RELEVANCE: Tuberculosis (TB) remains the leading cause of death due to bacterial infection. In spite of this, an effective vaccine against Mycobacterium tuberculosis (Mtb), the causative agent of TB, is lacking. Studies in humans have shown that various lipid components of the mycobacterial cell wall can be recognized by group 1 CD1-restricted T cells, however, the contribution of these T cells to immunity against Mtb is poorly understood. This study proposes to utilize novel animal models both to characterize the immune responses mediated by group 1 CD1-restricted T cells during Mtb infection, and to test the ability of lipid vaccines to confer resistance to Mtb infection.

描述(由申请人提供)：人类第1组CD1分子CD1a、CD1b和CD1c已被证明呈递内源性和分枝杆菌来源的脂类抗原给T细胞的不同亚群。第1组CD1限制性免疫反应与抗分枝杆菌免疫有关；然而，由于缺乏合适的动物模型，它们在感染中的作用尚不清楚。我们已经产生了转基因小鼠(HCD1Tg)，它们以类似于人类的模式表达人类第1组CD1分子，并支持仅限于第1组CD1的T细胞的发育。结核分枝杆菌(Mtb)感染和Mtb脂类免疫均可诱导hCD1Tg小鼠产生CD1限制性Mtb脂类抗原特异性T细胞反应，二次免疫比一次免疫更快。此外，hCD1Tg小鼠产生的第1组CD1限制性T细胞可以识别人类中描述的分枝杆菌抗原。综上所述，这些数据表明，第1组CD1限制性T细胞在获得性免疫中发挥作用，可以作为结核分枝杆菌疫苗开发的靶点。本研究旨在研究第1组CD1限制性T细胞在结核分枝杆菌感染过程中的体内功能，并利用hCD1Tg小鼠模型测试针对第1组CD1限制性T细胞的Mtb脂质疫苗的有效性。在目的1中，我们建议在结核分枝杆菌感染的hCD1Tg小鼠中鉴定1组CD1呈递的免疫优势结核分枝杆菌抗原，并评价这些抗原在脂肪疫苗中对结核分枝杆菌攻击的保护作用。在目标2中，我们建议建立表达不同Mtb脂类抗原特异性TCR的逆转录基因小鼠，并采用过继转移的方法研究这些T细胞的激活动力学、效应功能和保护作用。第1组CD1限制性MTB脂类抗原特异性T细胞直接识别外来抗原，而第1组CD1限制性自身反应性T细胞可能通过识别TLR成熟抗原提呈细胞呈递的内源性抗原而在感染过程中被激活，并参与先天抗分枝杆菌反应，类似于第2组CD1d限制性NKT细胞。因此，在我们的第三个目标中，我们将使用TCR转基因模型来研究结核分枝杆菌感染过程中自身反应第1组CD1限制性T细胞的发育需求和功能。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的保护性免疫，以及它们是否可以作为开发基于脂质抗原的结核分枝杆菌疫苗的靶点。 公共卫生相关性：结核病(TB)仍然是细菌感染导致的主要死亡原因。尽管如此，结核病的病原体结核分枝杆菌(Mtb)缺乏有效的疫苗。在人类中的研究表明，分枝杆菌细胞壁的各种脂质成分可以被第1组CD1限制性T细胞识别，然而，这些T细胞在抗结核分枝杆菌免疫中的作用尚不清楚。本研究建议利用新的动物模型来表征结核分枝杆菌感染过程中第一组CD1限制性T细胞介导的免疫反应，并测试脂肪疫苗对结核分枝杆菌感染的抵抗力。