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

基本信息

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
项目类别：
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

项目摘要

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 类 CD1 分子 CD1a、CD1b 和 CD1c 已被证明可将内源性和分枝杆菌衍生的脂质抗原呈递给各种 T 细胞亚群。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。我们已经培育出转基因小鼠 (hCD1Tg)，它们以与人类相似的模式表达人类 1 组 CD1 分子，并支持仅限于 1 组 CD1 的 T 细胞的发育。结核分枝杆菌 (Mtb) 感染和 Mtb 脂质免疫均可在 hCD1Tg 小鼠中引发第 1 组 CD1 限制性 Mtb 脂质抗原特异性 T 细胞反应，并且二次免疫比初次免疫诱导更快速的反应。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。总而言之，这些数据表明第 1 组 CD1 限制性 T 细胞在适应性免疫中发挥作用，并且可以作为 Mtb 疫苗开发的目标。该提案旨在研究 Mtb 感染期间 1 组 CD1 限制性 T 细胞的体内功能，并使用 hCD1Tg 小鼠模型测试针对 1 组 CD1 限制性 T 细胞的脂质疫苗的功效。在目标 1 中，我们建议鉴定 Mtb 感染的 hCD1Tg 小鼠中第 1 组 CD1 呈递的免疫显性 Mtb 抗原，并评估这些抗原在脂质疫苗中对 Mtb 攻击的保护功效。在目标 2 中，我们建议生成表达针对不同 Mtb 脂质抗原的 TCR 的逆转录小鼠，并使用过继转移方法研究这些 T 细胞的激活动力学、效应功能和保护作用。虽然第 1 组 CD1 限制性 Mtb 脂质抗原特异性 T 细胞直接识别外来抗原，但第 1 组 CD1 限制性自身反应性 T 细胞可能在感染过程中通过识别 TLR 成熟抗原呈递细胞呈递的内源性抗原而被激活，并有助于先天抗-分枝杆菌反应，类似于针对第 2 组 CD1d 限制性 NKT 细胞所描述的反应。因此，在我们的第三个目标中，我们将使用 TCR 转基因模型研究 Mtb 感染期间自身反应性 1 组 CD1 限制性 T 细胞的发育要求和功能。总的来说，这些研究将有助于更好地了解第 1 组 CD1 限制性 T 细胞如何有助于针对 Mtb 的保护性免疫，以及它们是否可以用于开发基于脂质抗原的 Mtb 疫苗。公共卫生相关性：结核病 (TB) 仍然是细菌感染导致死亡的主要原因。尽管如此，仍然缺乏针对结核病病原体结核分枝杆菌 (Mtb) 的有效疫苗。人类研究表明，分枝杆菌细胞壁的各种脂质成分可以被 1 类 CD1 限制性 T 细胞识别，然而，这些 T 细胞对 Mtb 免疫的贡献却知之甚少。本研究拟利用新型动物模型来表征 Mtb 感染期间由 1 组 CD1 限制性 T 细胞介导的免疫反应，并测试脂质疫苗赋予 Mtb 感染抵抗力的能力。