Role of IL-17 in Protective Vaccine-induced Immune Responses Against Tuberculosis

项目总结 结核分枝杆菌(Mtb)潜伏感染着世界上四分之一的人口，导致肺部 约900万人患有结核病，每年导致约130万人死亡1。当前可用的 结核疫苗，牛分枝杆菌卡介苗(BCG)，显示出不同的效果。此外，多重耐药 (MDR)结核分枝杆菌菌株最近出现。因此，非常需要新的结核病疫苗2。在美国的研究 在过去的十年中，主要利用诱导T辅助细胞1型(Th1)反应和产生 细胞因子干扰素-γ(干扰素γ)，作为tb3疫苗效力的读数。我们在前一年的学习 资助期表明，白介素17和辅助性T细胞17型(Th17)疫苗的反应至关重要 用于疫苗诱导的针对TB4-6的免疫。重要的是，我们最近证明了粘膜疫苗接种 结核分枝杆菌抗原与Th17诱导佐剂联合诱导强大的肺居留Th17细胞及改良卡介苗 结核分枝杆菌挑战4，6-8后疫苗诱导的保护。我们的机制研究表明，IL-17- 诱导趋化因子CXCL-136、9-11在结核分枝杆菌感染附近定位表达CXCR5的T细胞 巨噬细胞，导致肺淋巴滤泡的形成，并激活巨噬细胞介导结核分枝杆菌 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，但我们的 数据显示，在结核分枝杆菌感染后，疫苗诱导的Th17免疫反应在肺部积聚 速度不够，不足以提供“消毒”免疫力或完全控制结核分枝杆菌。在令人兴奋的新数据中 在之前的资金周期中产生的，我们证明了我们可以通过使用树突状细胞来克服这个瓶颈 (DC)通过激活内源性DC或将外源性激活的DC转移到 接种了疫苗的宿主，以实现更好的结核分枝杆菌控制6，13。因此，在此R01更新中建议的工作建立在 这些重要且高度相关的发现具有三个具体目标：具体目标1.识别早期 调节APC功能以促进Th17反应和诱导优势免疫的细胞因子途径 抗结核病。特定目标2.确定IL-23和IL-17依赖的调节Th17早期的机制 应对措施和结核病控制。特定目的3.鉴定新型C型凝集素受体激动剂Th17- 诱导结核病疫苗。结核分枝杆菌广泛耐药株(XDR)的出现，对其没有 目前存在的治疗方法，使得开发有效的结核病疫苗变得令人难以置信地紧迫。这项工作 这笔赠款中提出的将继续对未来疫苗战略的设计和使用产生重大影响 使我们能够促进IL-17的反应，以产生更好的、长期持久的疫苗诱导免疫 抗结核病。

PROJECT SUMMARY Mycobacterium tuberculosis (Mtb) latently infects one-fourth of the world’s population, causing pulmonary tuberculosis (TB) in ~9 million people and resulting in ~1.3 million deaths each year1. The currently available TB vaccine, Mycobacterium bovis BCG (BCG), shows variable efficacy. In addition, Multi-Drug-Resistant (MDR) Mtb strains have recently emerged. Thus, there is a great need for new TB vaccines2. Studies in the past decade have mainly utilized induction of T helper cell type 1 (Th1) responses and the production of the cytokine, Interferon-gamma (IFNγ), as readout for vaccine efficacy against TB3. Our studies during the prior funding period demonstrated that Interleukin (IL)-17 and T helper type 17 (Th17) vaccine responses are critical for vaccine-induced immunity against TB4-6. Importantly, we recently demonstrated that mucosal vaccination with the Mtb antigen with Th17-inducing adjuvants induced potent lung-resident Th17 cells and improved BCG vaccine-induced protection following Mtb challenge4,6-8. Our mechanistic studies demonstrated that IL-17- induced chemokines, including CXCL-136,9-11, localize CXCR5-expressing T cells near Mtb-infected macrophages, resulting in the formation of lung lymphoid follicles and activating macrophages to mediate Mtb control5,12. Despite these major advances in understanding the role of Th17 vaccine-induced cells in TB, our data show that upon Mtb infection, the accumulation of vaccine-induced Th17 immune responses in the lung is not accelerated enough to provide “sterilizing” immunity or complete Mtb control5. In exciting new data generated during the prior funding cycle, we show that we can overcome this bottleneck by using Dendritic Cell (DC) based therapy by either activating endogenous DCs, or transfer of exogenously activated DCs into vaccinated hosts, to achieve superior Mtb control6,13. Thus, the work proposed in this R01 renewal builds on these important and highly relevant findings with three Specific Aims: Specific Aim 1. Identifying the early cytokine pathways that modulate APC function to promote Th17 responses and induce superior immunity against TB. Specific Aim 2. Identifying the IL-23 and IL-17-dependent mechanisms that mediate early Th17 responses and Mtb control. Specific Aim 3. Identification of novel C-type lectin receptor agonists as Th17- inducing TB vaccines. The emergence of extensively drug-resistant strains (XDR) of Mtb, for which no treatments currently exist, makes the development of an effective TB vaccine incredibly urgent. The work proposed in this grant will continue to significantly impact the design and use of future vaccine strategies by allowing us to promote IL-17 responses to generate improved, long-term lasting vaccine-induced immunity against TB.