The regulation and functions of Group 1 CD1-restricted T cells

第 1 组 CD1 限制性 T 细胞的调节和功能

• 批准号: 10779737
• 负责人: Chyung-Ru Wang
• 金额: $ 66.57万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-20 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10779737
• 关键词: Activities of Daily Living; Acute; Affect; Antigen Presentation; Antigen-Presenting Cells; Antigens; Apolipoprotein E; Atherosclerosis; Attenuated; Autoimmune Diseases; Bone Marrow; CD1 Antigens; Cell Compartmentation; Cells; Cellular Metabolic Process; Characteristics; Chimera organism; Chronic; Chronic Phase; Clone Cells; Communicable Diseases; Data; Development; Diet; Disease; Exhibits; Family; Gene Expression Profile; General Population; Generations; Genetic Transcription; Growth; HIV; Health; Helper-Inducer T-Lymphocyte; High Fat Diet; Human; Hyperlipidemia; Immune response; Immunity; In Vitro; Individual; Infection; Inflammation; Kinetics; Lipids; Maintenance; Mediating; Memory; Modeling; Molecular; Molecular Profiling; Mus; Mycobacterium tuberculosis; Mycolic Acid; Pathogenicity; Pathway interactions; Peptides; Phenotype; Phospholipids; Play; Population; Property; Psoriasis; Pulmonary Inflammation; Regulation; Role; Signal Transduction; Skin; Specificity; T cell response; T memory cell; T-Lymphocyte; T-Lymphocyte Subsets; Thymus Gland; Transgenic Mice; Transgenic Model; Tuberculosis; Vaccinated; Vaccination; Work; antigen-specific T cells; autoreactive T cell; autoreactivity; comorbidity; feeding; glucose mycolate; in vivo; insight; member; microbial; mouse model; nanoparticle; novel; response; transcriptome; tuberculosis immunity; vaccine development

PROJECT SUMMARY Group 1 CD1-restricted T cells are members of the unconventional T cell family that recognize self- and microbial lipid antigens presented by CD1a, CD1b, and CD1c molecules. Group 1 CD1-restricted T cells have been implicated to play critical roles in various autoimmune and infectious diseases, in particular Mycobacterium tuberculosis (Mtb) infection. While group 1 CD1-restricted T cells represent a substantial part of the T cell repertoire in humans, further understanding of their in vivo function and regulation in immune response has been stymied by the lack of group 1 CD1 expression in mice. We have previously generated a transgenic mouse model possessing the entire human group 1 CD1 locus (hCD1Tg) and TCR transgenic mouse models with Mtb lipid and self-lipid specificity. We demonstrated that both mycolic acid (MA)-specific and self-lipid-specific CD1b-restricted T cells confers protection against Mtb infection. In addition, chronic activation of CD1b autoreactive T cells can lead to the development of psoriasis-like skin inflammation in an ApoE-deficient mouse model of hyperlipidemia. As hyperlipidemia is a common condition in HIV-infected individuals and the general population, we aim to further understand how it may affect the function of group 1 CD1-restricted T cells during infection using Mtb infection as a model. In Aim 1, TCR transgenic mouse models in hCD1Tg/LDLR-/- background will be used to determine the impact of diet- induced hyperlipidemia on self- and microbial lipid-specific T cells and elucidate the molecular and cellular mechanisms mediate such effect. The impact of hyperlipidemia on the polyclonal group 1 CD1-restricted T cell responses to Mtb infection will also be determined by comparing bacterial burden, lung inflammation, and magnitude of autoreactive and Mtb lipid-specific T cell responses in Mtb-infected hCD1Tg/LDLR-/- mice with or without hyperlipidemia. While peptide-specific T cells are known to have distinct effector and memory phenotypes, the properties of memory group 1 CD1-restricted T cells remain elusive. In Aim 2, we will determine functional properties and protective mechanism of memory MA/CD1b-specific T cells generated in mice vaccinated with MA containing nanoparticle (MA-NP). To identify common features associated with Mtb-lipid specific memory T cells, we will compare memory MA/CD1b-specific T cells to glucose monomycolate/CD1b-specific T cells, isolated from a novel TCR transgenic mouse model expressing a conserved germline-encoded mycolyl lipid-reactive (GEM) TCR. Lasty, the transcriptional and functional properties of memory MA/CD1b-specific T cells elicited by two vaccination approaches, MA-NP and an attenuated Mtb strain, will be compared and their response to subsequent challenge with Mtb will be evaluated. Collectively, these studies will pave way to better understanding of the role of lipid-specific T cells in various infectious disease in a relevant comorbidity condition.

项目概要 第 1 组 CD1 限制性 T 细胞是非常规 T 细胞家族的成员，可识别自身和 由 CD1a、CD1b 和 CD1c 分子呈递的微生物脂质抗原。第 1 组 CD1 限制性 T 细胞 已被认为在各种自身免疫性疾病和传染病中发挥着关键作用，特别是 结核分枝杆菌 (Mtb) 感染。虽然第 1 组 CD1 限制性 T 细胞代表了大量 人类 T 细胞库的一部分，进一步了解它们的体内功能和调节 小鼠体内缺乏第 1 组 CD1 表达，从而阻碍了免疫反应。我们之前有过 生成了拥有整个人类 1 组 CD1 基因座 (hCD1Tg) 和 TCR 的转基因小鼠模型 具有 Mtb 脂质和自身脂质特异性的转基因小鼠模型。我们证明了分枝菌酸 (MA) 特异性和自身脂质特异性 CD1b 限制性 T 细胞可提供针对 Mtb 感染的保护。在 此外，CD1b自身反应性T细胞的慢性激活可导致银屑病样皮肤的发展 ApoE 缺陷小鼠高脂血症模型中的炎症。由于高脂血症是一种常见病 在艾滋病毒感染者和普通人群中，我们的目标是进一步了解它如何影响 使用 Mtb 感染作为模型，研究感染过程中第 1 组 CD1 限制性 T 细胞的功能。在目标 1 中，TCR hCD1Tg/LDLR-/-背景的转基因小鼠模型将用于确定饮食-/-的影响 在自身和微生物脂质特异性 T 细胞上诱导高脂血症，并阐明分子和细胞 机制介导这种效应。高脂血症对多克隆1型CD1限制性T细胞的影响 细胞对 Mtb 感染的反应也将通过比较细菌负荷、肺部炎症、 感染 Mtb 的 hCD1Tg/LDLR-/- 小鼠中自身反应性和 Mtb 脂质特异性 T 细胞反应的强度和强度 有或没有高脂血症。虽然已知肽特异性 T 细胞具有独特的效应和记忆 尽管表型不同，但记忆组 1 CD1 限制性 T 细胞的特性仍然难以捉摸。在目标 2 中，我们将 确定所生成的记忆 MA/CD1b 特异性 T 细胞的功能特性和保护机制 在接种了含有 MA 的纳米颗粒 (MA-NP) 的小鼠中。识别与相关的共同特征 Mtb-脂质特异性记忆 T 细胞，我们将记忆 MA/CD1b 特异性 T 细胞与葡萄糖进行比较 单菌酸/CD1b 特异性 T 细胞，从表达 a 的新型 TCR 转基因小鼠模型中分离出来 保守的种系编码的菌基脂质反应性 (GEM) TCR。 Lasty，转录和功能 两种疫苗接种方法（MA-NP 和 减毒 Mtb 菌株，将进行比较，并且它们对随后 Mtb 攻击的反应将是 评价。总的来说，这些研究将为更好地理解脂质特异性 T 的作用铺平道路。 各种传染病中相关合并症的细胞。