Role of IL-17 in protective vaccine-induced immune responses against tuberculosis

项目概述：结核病（TB）的病原体结核分枝杆菌（Mtb）， 全球每年超过200万人。牛分枝杆菌BCG是唯一可用的结核病疫苗，其效力有限。 无法有效治疗的极端耐药（XDR）和多药耐药（MDR）的出现 结核分枝杆菌菌株的发现强调了对有效结核疫苗的需求。尽管发现了几个 有希望的Mtb抗原候选疫苗，我们的认识不足，要求早期有效 对Mtb的记忆应答仍然是开发有效疫苗策略的重大挑战。 产生干扰素-γ（IFN）的辅助性T细胞1（Th 1）记忆细胞是有效保护 TB.然而，我们最近报道了一种产生白细胞介素（IL）-17的CD 4 + T辅助细胞（Th 17）记忆细胞， Th 1记忆细胞的积累和对Mtb攻击的保护性记忆应答所需。我们 假设针对TB的成功疫苗接种需要Th 17记忆细胞。根据该 假设，用Mtb抗原接种导致抗原特异性Th 17和Th 1 CD 4+的产生 细胞，Th 17细胞被隔离在肺中。在随后用Mtb激发后，肺驻留Th 17 记忆细胞迅速增殖，产生IL-17并触发趋化因子的局部表达。我们将 在三个目标中检验这个假设。目标1：确定有效Th 17记忆所需的特定因素 Mtb攻毒后的反应。目的2：Th 17记忆细胞介导Th 1的机制 积累目的3：确定增加Th 17肺常住人口是否会改善疫苗- 诱导对结核病的保护。这项资助中提出的工作将对未来的设计产生重大影响。 通过使我们能够靶向IL-17，长期目标是改善针对 人类的结核病

Project summary: Mycobacterium tuberculosis (Mtb), the causative agent of Tuberculosis (TB), kills more than 2 million people worldwide annually. M.bovis BCG, the only TB vaccine available, is of limited efficacy. The emergence of effectively untreatable extremely drug resistant (XDR) and multi-drug resistant (MDR) strains of Mtb underscores the requirement for an effective TB vaccine. Despite identification of several promising Mtb antigen vaccine candidates, our poor understanding of the requirements of early and effective memory responses to Mtb remains a significant challenge to the development of effective vaccine strategies. Interferon-gamma (IFN )-producing T helper 1(Th1) memory cells are required for effective protection against TB. However, we recently reported that an Interleukin (IL)-17-producing CD4+ T helper (Th17) memory cells are required for accumulation of Th1 memory cells and protective memory responses to Mtb challenge. We hypothesize that successful vaccination against TB requires Th17 memory cells. According to this hypothesis, vaccination with Mtb antigen results in the generation of antigen specific-Th17 and Th1 CD4+ cells, the Th17 cells being sequestered in the lung. Upon subsequent challenge with Mtb, lung resident Th17 memory cells proliferate rapidly, producing IL-17 and triggering the local expression of chemokines. We will test this hypothesis in three aims. Aim 1: Identifying the specific factors required for effective Th17 memory response following Mtb challenge. Aim 2: The mechanism by which Th17 memory cells mediate Th1 accumulation. Aim 3: To determine whether increasing the Th17 lung resident population improves vaccine- induced protection against TB. The work proposed in this grant will significantly impact the design of future vaccine strategies by allowing us to target IL-17 with the long-term goal of improving vaccine strategies against TB in humans.