ROLE OF IL-17 IN PROTECTIVE VACCINE-INDUCED IMMUNE RESPONSES AGAINST TUBERCULOSIS

 描述（由申请人提供）：世界上大约三分之一的人口潜伏性感染结核分枝杆菌（Mtb），一生中发生肺结核（TB）的风险为10%。耐药结核菌株的出现和目前可用的疫苗M.牛卡介苗（BCG）。因此，开发有效的疫苗对于消除结核病这一公共卫生问题至关重要。过去十年的研究主要利用辅助性T细胞1（Th 1）应答的诱导和干扰素γ（IFNγ）的产生作为针对TB的疫苗效力的读数。然而，尽管诱导高水平的IFN-γ，MVA 85 A，第一个在人体临床试验中测试的重组TB疫苗，未能保护免受TB疾病。 这些数据强调了探索新方法以提高疫苗诱导的抗结核免疫力的重要性。在之前的资助期间，我们证明了产生细胞因子白细胞介素-17（IL-17）的辅助性T细胞17型（Th 17）是介导疫苗诱导的抗Mtb保护的主要效应细胞。尽管IFNγ对于疫苗诱导的抗TB免疫是必需的，但疫苗诱导的Th 17细胞产生的IL-17对于赋予疫苗诱导的抗TB保护是绝对必要的。重要的是，Mtb抗原在佐剂中的粘膜疫苗接种诱导了有效的肺驻留Th 17细胞，并改善了Mtb攻击后BCG疫苗诱导的保护。我们的机制研究表明，IL-17诱导趋化因子，包括CXCL-13，定位CXCR 5表达的T细胞附近的结核分枝杆菌感染的巨噬细胞，导致淋巴滤泡的形成和激活巨噬细胞介导结核分枝杆菌的控制。尽管在理解Th 17疫苗诱导的细胞在TB中的作用方面取得了这些重大进展，但疫苗诱导的Th 17回忆应答在肺中的积累并没有加速到足以提供对Mtb感染的杀菌免疫。然而，我们表明，疫苗诱导的Th 17免疫可以利用DC疗法来实现对Mtb攻击的近杀菌免疫。因此，在本次更新中，在目标1中，我们将首先确定通过调节抗原呈递细胞（APC）功能来加速Th 17细胞积累是否会改善Mtb控制。在目标2中，我们将阐述IL-17在接种疫苗的小鼠中DC治疗中的功能作用，以及IL-17启动子中的单核苷酸多态性（SNP）与人类疫苗诱导的应答之间的关系。最后，在目标3中，我们将鉴定并将有效的Th 17诱导佐剂纳入保护性粘膜TB疫苗中，以转化为未来在人类中的使用。这些目标将使用新型Mtb T细胞受体（TCR）转基因（Tg）小鼠模型与基因缺陷小鼠、Mtb感染小鼠模型、新型佐剂和疫苗接种策略以及人类假设检验来解决。这项拨款中提出的工作将使我们能够促进Th 17反应，以产生针对结核病的持久疫苗诱导免疫力。

 DESCRIPTION (provided by applicant): Approximately one-third of the world's population is latently infected with Mycobacterium tuberculosis (Mtb) with a 10% risk of developing pulmonary tuberculosis (TB) over their lifetime. Global efforts to combat TB are hampered by the emergence of drug-resistant strains of Mtb and variable efficacy of the currently available vaccine, M. bovis BCG (BCG). Thus, the development of an effective vaccine is critical for the elimination of TB as a public health problem. Studies in the past decade have mainly utilized induction of T helper 1 (Th1) responses and production of interferon gamma (IFNγ) as readouts for vaccine efficacy against TB. However, despite inducing high levels of IFN-γ, MVA85A, the first recombinant TB vaccine tested in human clinical trials, failed to protect against TB disease. These data highlight the importance of exploring new approaches to improve vaccine-induced immunity against TB. During the prior funding period, we demonstrated that T helper type 17 (Th17) cells, which produce the cytokine interleukin-17 (IL-17), are the primary effector cell mediating vaccine-induced protection against Mtb. Although IFNγ is dispensable for vaccine-induced immunity against TB, IL-17 production by vaccine-induced Th17 cells is absolutely necessary to confer vaccine-induced protection against TB. Importantly, mucosal vaccination with the Mtb antigen in adjuvant induced potent lung-resident Th17 cells and improved BCG vaccine-induced protection following Mtb challenge. Our mechanistic studies showed that IL-17 induced chemokines, including CXCL-13, to localize CXCR5-expressing T cells near Mtb-infected macrophages, resulting in the formation of lymphoid follicles and activating macrophages to mediate Mtb control. Despite these major advances in understanding the role of Th17 vaccine-induced cells in TB, the accumulation of vaccine-induced Th17 recall responses in the lung is not accelerated enough to provide sterilizing immunity to Mtb infection. However, we show that vaccine-induced Th17 immunity can be harnessed using DC therapy to achieve near sterilizing immunity against Mtb challenge. Thus, in this renewal, in Aim 1, we will first determine if accelerating Th17 cell accumulation by modulating antigen-presenting cell (APC) function will improve Mtb control. In Aim 2, we will address the functional role of IL-17 in DC therapy in vaccinated mice, and the relationship between a Single Nucleotide Polymorphism (SNP) in the IL-17 promoter and vaccine-induced responses in humans. Finally, in Aim 3, we will identify and incorporate potent Th17- inducing adjuvants into protective mucosal TB vaccines to translate for future use in humans. These objectives will be addressed using novel Mtb T-cell receptor (TCR) transgenic (Tg) mouse models in combination with gene-deficient mice, mouse models of Mtb infection, novel adjuvants and vaccination strategies, and hypothesis testing in humans. The work proposed in this grant will allow us to promote Th17 responses to generate long-lasting vaccine-induced immunity against TB.