The Role of Lipid-specific T cells in Mediating Protection Against M. tuberculosis

脂质特异性 T 细胞在介导结核分枝杆菌保护中的作用

• 批准号: 10415830
• 负责人: CHETAN SESHADRI
• 金额: $ 80.56万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10415830
• 关键词: Address; Adoptive Transfer; Adult; Aerosols; Animal Model; Animal Testing; Animals; Antigen Targeting; Antigen-Presenting Cells; Antigens; Autoimmunity; BCG Live; Bacille Calmette-Guerin vaccination; CD1 Antigens; Cause of Death; Cell Wall; Cells; Cessation of life; Child; Communicable Diseases; Communities; Computational Technique; Computing Methodologies; Core Facility; Cutaneous; Data; Development; Disease; Epidemic; Epitopes; Flow Cytometry; Foundations; Frequencies; Funding; Glycolipids; Goals; Histocompatibility; Human; Immune system; Immunity; Infection; Intravenous; Jurkat Cells; Lipids; Lung; Macaca mulatta; Malignant Neoplasms; Mediating; Memory; Modeling; Mus; Mycobacterium Infections; Mycobacterium bovis; Mycobacterium tuberculosis; Mycobacterium tuberculosis antigens; Mycolic Acid; Pathogenesis; Peptides; Phase; Phenotype; Proliferating; Proteins; Pulmonary Tuberculosis; Research; Role; Route; Specificity; Stains; Study models; System; T cell response; T-Cell Antigen Receptor Specificity; T-Cell Receptor; T-Lymphocyte; Testing; Tissues; Transgenic Organisms; Tuberculosis; Tuberculosis Vaccines; United States National Institutes of Health; Vaccinated; Vaccination; Vaccines; Waxes; Whole Cell Vaccine; antigen binding; antigen-specific T cells; antimicrobial; clinical efficacy; efficacy study; efficacy testing; experimental study; infectious disease model; mouse model; mycobacterial; nonhuman primate; novel vaccines; prevent; public health relevance; tool; unvaccinated

PROJECT SUMMARY (ABSTRACT) ! Mycobacterium tuberculosis (M.tb) was responsible for more than 1.6 million deaths in 2017, making it a leading infectious cause of death worldwide. Currently, Mycobacterium bovis bacille Calmette-Guérin (BCG) is the only licensed vaccine for tuberculosis. BCG provides protection against disseminated forms of the disease in children but is inconsistent in preventing the development of pulmonary tuberculosis in adults. Since adults with pulmonary tuberculosis are highly infectious, control of the epidemic will not be achieved with BCG, and new vaccines are urgently needed. A number of lines of evidence from human and animal studies have revealed the critical importance of T cells in conferring protective immunity to M.tb. However, we still do not know which M.tb antigens are targeted by the T cells that confer protection. This information is critical to developing new vaccines that are more effective than BCG. Classically, T cells are activated by foreign peptide antigens that are bound to highly polymorphic major histocompatibility (MHC) molecules. Alternatively, mycobacterial cell wall lipids have conclusively been shown to activate human T cells when bound to CD1 proteins on antigen- presenting cells. The CD1 system has been shown to mediate protective T-cell responses in mouse models of autoimmunity, cancer, and infectious diseases. However, the lack of an appropriate animal model has impeded research into the importance of CD1-restricted T cells in the pathogenesis of M.tb. Tools to identify CD1- restricted T cells were also unavailable until recently. Over the last ten years, we have established lipid-loaded CD1 tetramers as tools to study the phenotypes and functions of CD1-restricted T cells in humans. We have also developed and validated a humanized CD1 transgenic (hCD1Tg) mouse model and shown that T-cells specific for mycolic acid, a major constituent of the mycobacterial cell wall, confer protective immunity to M.tb challenge. Finally, we are now also developing CD1 tetramers for non-human primate (NHP) models of TB. These preliminary data establish the feasibility of developing small and large animal models for studying the role of CD1-restricted T cells in TB pathogenesis. In Aim 1, we will validate a suite of human CD1 tetramers loaded with synthetic lipid antigens and determine the tissue-specific phenotypes and functions of CD1-restricted T cells after mycobacterial vaccination or infection of hCD1Tg mice and NHP. In Aim 2, we will explore whether BCG administered by different routes (cutaneous, aerosol, or intravenous) or primary M.tb infection induces lipid- specific T cells that confer protective immunity to M.tb challenge in hCD1Tg mice and NHP. We will also study whether lipid antigen-specific T cells confer protective immunity using adoptive transfer experiments in hCD1Tg mice. By the end of the funding period, we will have validated a set of tools that will be available to the broader TB research community and addressed whether lipid-specific T cells should be considered a correlate of protective immunity in Phase II/III clinical efficacy studies of whole cell mycobacterial vaccines.

项目概要（摘要） ！ 2017 年，结核分枝杆菌 (M.tb) 导致超过 160 万人死亡，使其成为 全球主要的传染性死亡原因。目前，牛分枝杆菌卡介苗（BCG） 唯一获得许可的结核病疫苗。卡介苗可预防疾病的传播形式 但在预防成人肺结核的发展方面却不一致。自从成人 肺结核传染性强，卡介苗无法控制疫情， 迫切需要新疫苗。来自人类和动物研究的一系列证据表明 T 细胞在赋予结核分枝杆菌保护性免疫力方面至关重要。然而，我们仍然不知道是哪一个 M.tb 抗原是提供保护的 T 细胞的目标。这些信息对于开发新产品至关重要 比卡介苗更有效的疫苗。传统上，T 细胞被外源肽抗原激活， 与高度多态的主要组织相容性 (MHC) 分子结合。或者，分枝杆菌细胞壁 已最终证明，当脂质与抗原上的 CD1 蛋白结合时，可以激活人类 T 细胞。 呈现细胞。 CD1 系统已被证明可以在小鼠模型中介导保护性 T 细胞反应 自身免疫、癌症和传染病。然而，由于缺乏合适的动物模型，阻碍了 研究 CD1 限制性 T 细胞在结核分枝杆菌发病机制中的重要性。识别 CD1- 的工具 直到最近，限制性 T 细胞也无法获得。在过去的十年里，我们已经建立了脂质负载 CD1 四聚体作为研究人类 CD1 限制性 T 细胞表型和功能的工具。我们有 还开发并验证了人源化 CD1 转基因 (hCD1Tg) 小鼠模型，并表明 T 细胞 对分枝杆菌酸（分枝杆菌细胞壁的主要成分）具有特异性，赋予对结核分枝杆菌的保护性免疫力 挑战。最后，我们现在还在开发用于非人灵长类 (NHP) 结核病模型的 CD1 四聚体。 这些初步数据确立了开发小型和大型动物模型以研究其作用的可行性 CD1 限制性 T 细胞在结核病发病机制中的作用。在目标 1 中，我们将验证加载的一套人类 CD1 四聚体 使用合成脂质抗原并确定 CD1 限制性 T 细胞的组织特异性表型和功能 分枝杆菌疫苗接种或 hCD1Tg 小鼠和 NHP 感染后。在目标 2 中，我们将探讨 BCG 是否 通过不同途径（皮肤、气雾剂或静脉注射）给药或原发性结核分枝杆菌感染会诱导脂质 赋予 hCD1Tg 小鼠和 NHP 的 M.tb 攻击保护性免疫的特异性 T 细胞。我们也会学习 脂质抗原特异性 T 细胞是否通过 hCD1Tg 过继转移实验赋予保护性免疫 老鼠。到资助期结束时，我们将验证一套工具，可供更广泛的人使用。 结核病研究界并讨论了脂质特异性 T 细胞是否应被视为与 全细胞分枝杆菌疫苗II/III期临床疗效研究中的保护性免疫。