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感染结核分枝杆菌(Mtb)，一生中有10%的风险发展为肺结核(TB)。全球抗击结核病的努力因结核分枝杆菌耐药株的出现和现有疫苗卡介苗(BCG)的不同效力而受到阻碍。因此，开发一种有效的疫苗对于消除结核病这一公共卫生问题至关重要。在过去的十年中，研究主要利用T辅助细胞(Th1)反应的诱导和干扰素γ的产生作为结核病疫苗疗效的读数。然而，尽管诱导了高水平的干扰素-γ，MVA85A，第一个在人类临床试验中测试的重组结核病疫苗，却未能预防结核病。 这些数据突显了探索提高疫苗诱导的结核病免疫力的新方法的重要性。在之前的资助期间，我们证明了产生细胞因子白介素17(IL-17)的辅助性T细胞17(Th17)是介导疫苗诱导的抗结核分枝杆菌保护的主要效应细胞。虽然干扰素γ在疫苗诱导的抗结核免疫中是必不可少的，但疫苗诱导的Th17细胞产生IL-17对于疫苗诱导的抗结核保护是绝对必要的。重要的是，粘膜接种结核分枝杆菌抗原在佐剂中诱导了强大的驻肺Th17细胞，并改善了卡介苗对结核分枝杆菌攻击后的保护作用。我们的机制研究表明，IL-17诱导包括CXCL-13在内的趋化因子将表达CXCR5的T细胞定位在结核杆菌感染的巨噬细胞附近，导致淋巴滤泡的形成，并激活巨噬细胞以介导结核分枝杆菌的控制。尽管在理解Th17疫苗诱导的细胞在结核病中的作用方面取得了这些重大进展，但疫苗诱导的Th17回忆反应在肺中的积累速度还不够快，不足以提供对结核分枝杆菌感染的灭菌免疫力。然而，我们表明，疫苗诱导的Th17免疫可以利用DC疗法来实现对结核分枝杆菌攻击的近乎灭菌的免疫。因此，在这次更新中，在目标1中，我们将首先确定通过调节抗原提呈细胞(APC)功能来加速Th17细胞聚集是否会改善结核分枝杆菌的控制。在目标2中，我们将讨论IL-17在免疫小鼠DC治疗中的功能作用，以及IL-17启动子上的单核苷酸多态性(SNP)与疫苗诱导的人类反应之间的关系。最后，在目标3中，我们将确定有效的Th17诱导佐剂并将其纳入保护性粘膜结核病疫苗中，以转化为未来在人类身上使用。这些目标将使用新型结核分枝杆菌T细胞受体(TCR)转基因(TG)小鼠模型与基因缺陷小鼠相结合，Mtb感染的小鼠模型，新的佐剂和疫苗接种策略，以及人类的假设检验来解决。这项赠款中提议的工作将使我们能够促进Th17反应，以产生针对结核病的持久疫苗诱导免疫。

 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.