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，每年在全世界造成200多万人死亡。M.唯一可用的结核病疫苗-牛卡介苗-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强调了对有效结核疫苗的需求。尽管鉴定了几种有希望的Mtb抗原疫苗候选物，但我们对Mtb的早期和有效记忆应答的要求的了解不多仍然是开发有效疫苗策略的重大挑战。干扰素-γ（IFN？）-产生T辅助1（Th 1）记忆细胞是有效保护免受TB所需的。然而，我们最近报道，白细胞介素（IL）-17-产生的CD 4 + T辅助细胞（Th 17）的记忆细胞所需的积累的Th 1记忆细胞和保护性记忆反应的结核分枝杆菌的挑战。我们假设成功的结核病疫苗接种需要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+细胞的产生，Th 17细胞被隔离在肺中。在随后用Mtb攻击时，肺驻留的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。我们将从三个方面来检验这一假设。目的1：确定Mtb攻击后有效Th 17记忆应答所需的特定因素。目的2：Th 17记忆细胞介导Th 1蓄积的机制。目的3：确定增加Th 17肺居民群体是否改善疫苗诱导的针对TB的保护。这项资助中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，长期目标是改善人类结核病疫苗策略。 公共卫生相关性：结核病（TB），由微生物M引起。结核病（Mtb）每年在全世界造成200多万人死亡。为了改进结核病的免疫策略，我们必须了解在肺中诱导抗结核病的长期有效免疫的基本要求。这项工作与公共卫生的相关性在于，它将显著影响未来疫苗策略的设计，使我们能够改善疫苗诱导的Th 17应答，从而产生更好的疫苗诱导的抗结核免疫力，因此有可能降低结核病的发病率。

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.