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

项目摘要 结核分枝杆菌（Mtb）潜伏感染世界四分之一的人口，引起肺结核。 结核病（TB）每年约有900万人，导致约130万人死亡1。当前可用的 结核病疫苗，牛分枝杆菌BCG（BCG），表现出不同的疗效。此外，多重耐药 (MDR)结核病菌株最近出现了。因此，非常需要新的结核病疫苗2。的研究 在过去的十年中，主要利用T辅助细胞1型（Th 1）应答的诱导和 细胞因子，干扰素-γ（IFNγ），作为针对TB 3的疫苗功效的读数。我们的研究在过去的 资助期间表明，白细胞介素（IL）-17和17型辅助性T细胞（Th 17）疫苗反应至关重要 用于疫苗诱导的抗TB 4 -6的免疫。重要的是，我们最近证明粘膜接种 用Mtb抗原和Th 17诱导佐剂诱导有效的肺驻留Th 17细胞和改进的BCG Mtb攻击后疫苗诱导的保护4，6-8。我们的机制研究表明，IL-17- 诱导的趋化因子，包括CXCL-136，9 -11，将表达CXCR 5的T细胞定位于Mtb感染的 巨噬细胞，导致肺淋巴滤泡的形成并激活巨噬细胞介导Mtb 控制5，12。尽管在理解Th 17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，但我们的研究表明， 数据显示，在Mtb感染后，疫苗诱导的Th 17免疫应答在肺中的积累是 加速不足以提供“灭菌”免疫或完全的Mtb控制5。令人兴奋的新数据 在前一个资金周期中产生的，我们表明，我们可以通过使用树突状细胞克服这一瓶颈， (DC)通过激活内源性DC或将外源性激活的DC转移到细胞内， 接种宿主，以实现上级Mtb控制6，13.因此，本次R 01更新中提出的工作基于 这些重要且高度相关的发现有三个具体目标：具体目标1。识别早期 调节APC功能以促进Th 17应答并诱导上级免疫的细胞因子途径 对抗结核病。具体目标2。鉴定介导早期Th 17的IL-23和IL-17依赖性机制 Mtb控制。具体目标3。新型C型凝集素受体激动剂Th 17的鉴定- 诱导结核病疫苗。结核分枝杆菌广泛耐药菌株（XDR）的出现， 目前存在的治疗方法，使得开发有效的结核病疫苗变得非常紧迫。工作 这项赠款中提出的建议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应答，以产生改善的、长期持久的疫苗诱导的免疫力， 对抗结核病。

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.