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

描述（由申请人提供）：结核分枝杆菌（Mtb）是结核病（TB）的病原体，每年在全球造成200多万人死亡。牛分枝杆菌卡介苗是唯一可用的结核病疫苗，效力有限。无法有效治疗的极端耐药（XDR）和多重耐药（MDR）结核分枝杆菌菌株的出现，突出表明需要一种有效的结核病疫苗。尽管确定了几种有希望的Mtb抗原候选疫苗，但我们对Mtb早期和有效记忆反应的要求了解不足，仍然是开发有效疫苗策略的重大挑战。移行细胞(干扰素吗?)-产生T辅助1（Th1）记忆细胞是有效预防结核病所必需的。然而，我们最近报道了产生白细胞介素(IL)-17的CD4+ T辅助（Th17）记忆细胞是Th1记忆细胞积累和对Mtb挑战的保护性记忆反应所必需的。我们假设成功的结核病疫苗接种需要Th17记忆细胞。根据这一假设，接种Mtb抗原导致抗原特异性Th17和Th1 CD4+细胞的产生，Th17细胞被隔离在肺中。在随后的Mtb攻击后，肺常驻Th17记忆细胞迅速增殖，产生IL-17并触发局部趋化因子的表达。我们将用三个目标来检验这一假设。目的1：确定Mtb挑战后有效Th17记忆反应所需的具体因素。目的2:Th17记忆细胞介导Th1积累的机制。目的3：确定增加Th17肺常住人口是否能提高疫苗诱导的结核病保护作用。这项资助提出的工作将显著影响未来疫苗策略的设计，使我们能够以IL-17为目标，改善人类结核病疫苗策略的长期目标。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Tuberculosis(TB), caused by the organism M. tuberculosis (Mtb) kills more than 2 million people worldwide every year. To improve immunization strategies against TB, it important for us to understand the basic requirements for induction of long-lived effective immunity in the lung against TB. The relevance of this work to public health is that it will significantly impact the design of future vaccine strategies by allowing us to improve vaccine-induced Th17 responses to generate better vaccine-induced immunity against TB will therefore have the potential to reduce the incidence of TB.