Novel IL-17 producing memory cells are key to vaccine-based immunity in the lung

项目概述：结核病（TB）每年在全球范围内造成200多万人死亡。唯一的TB 卡介苗（BCG）具有不同的功效，这促使人们寻找 更有效的疫苗。虽然在分枝杆菌的鉴定方面取得了重大进展， 结核病（Mtb）抗原候选人，一个重大的障碍，成功的疫苗设计仍然是我们的穷人 了解记忆反应如何介导肺保护。长期目标是 建议是定义肺中诱导保护性记忆免疫的基本要求， 肺病原体如Mtb.对结核病的保护性召回反应与外观有关 产生干扰素（IFN）-γ的CD 4 + T细胞，许多研究都集中在诱导这些细胞在 改善疫苗接种的希望。不幸的是，与BCG介导的相比，没有发生改善。是 因此，其他因素可能在保护性记忆中发挥作用， 以及如何调节它们将导致疫苗效力的实质性改善。在这方面 我们最近发现，产生白细胞介素（IU-17）的记忆细胞先于IFN-γ记忆细胞， 在肺中的IFN-γ记忆应答，并且在不存在这些细胞的情况下，IFN-γ记忆应答不发生。 根据初步数据，我们提出了结核病疫苗诱导保护的三阶段模型。首先 疫苗接种诱导IFN-γ和IL-17产生细胞，但只有IL-17产生细胞在非炎症的 肺。在用Mtb攻击时，肺驻留记忆细胞产生IL-17并触发局部免疫应答。 趋化因子的表达（阶段1）。趋化因子梯度从淋巴细胞中吸引IFN-γ记忆细胞， 池（第2阶段）。反过来，这些IFN-γ细胞激活肺中的骨髓细胞以停止Mtb生长（阶段3）。的 缺乏有效的IL-17应答（阶段1）消除了接种疫苗的小鼠产生免疫应答的能力。 对Mtb攻击的保护性回忆免疫应答（阶段2和3）。肺内IL-17- 通过接种疫苗产生CD 4+记忆细胞的产生群体，并且这些细胞是免疫系统的关键。 疫苗诱导的抗结核保护的组成部分是完全新颖的。确定具体因素， 对于这些细胞在接种后在肺中的持久性和存活是至关重要的。我们 提出两个目标。目的一：研究IL-17产生细胞存活和维持所需的因素， 将研究肺中的记忆细胞。在目标二中，细胞的位置和影响细胞的因素 将确定该群体在肺中的建立。这项工作与公共卫生的相关性 它将促进疫苗战略的合理发展，因此有可能 降低结核病的发病率。

Project summary: Tuberculosis (TB) kills more than 2 million people every year worldwide. The only TB vaccine available, Bacille Calmette Guerin (BCG) has variable efficacy and this has prompted the search for more effective vaccines. Although significant progress has been made in identification of Mycobacterium tuberculosis (Mtb) antigen candidates, a significant hurdle to successful vaccine design remains our poor understanding of how the memory response mediates protection in the lung. The long-term goal of this proposal is to define the basic requirements for induction of protective memory immunity in the lung against pulmonary pathogens such as Mtb. The protective recall response to TB is associated with the appearance of CD4+ T cells that produce interferon (IFN)-y and many studies have focused on inducing these cells in the hope of improving vaccination. Unfortunately improvement over that mediated by BCG has not occurred. It is possible therefore that other factors play a role in protective memory and that determining what these factors are and how they can be modulated will lead to substantial improvement in vaccine efficacy. In this regard we have recently found that interleukin (IU-17-producina memory cells precede the IFN-Y memory cell response in the lung, and that in the absence of these cells the IFN-v memory response does not occur. Based on preliminary data we propose a three-phase model of vaccine-induced protection in TB. Firstly vaccination induces both IFN-y and IL-17-producing cells but only IL-17-producing cells populate the noninflamed lung. Upon challenge with Mtb, the lung resident memory cells produce IL-17 and trigger local expression of chemokines (phase 1). The chemokine gradient attracts IFN-y memory cells from the lymphoid pool (phase 2). In turn, these IFN-y cells activate myeloid cells in the lung to halt Mtb growth (phase 3). The absence of an effective IL-17 response (phase 1) ablates the ability of vaccinated mice to generate a protective recall immune response to Mtb challenge (phases 2 and 3). The finding that a lung-resident IL-17- producing population of CD4+ memory cells is generated by vaccination and that these cells are a critical component of vaccine-induced protection against TB is entirely novel. Determining the specific factors that are required for the persistence and survival of these cells in the lung following vaccination is crucial. We propose two aims. In Aim One the factors required for the survival and maintenance of IL-17-producing memory cells in the lung will be investigated. In Aim two, the location of the cells and the factors that impact the establishment of this population in the lung will be determined. The relevance of this work to public health is that it will promote rational development of vaccine strategies and will therefore have the potential to reduce the incidence of TB.