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

项目简介：结核病（TB）每年在全世界造成200多万人死亡。卡介苗（BCG）是唯一可用的结核病疫苗，其功效各不相同，这促使人们寻找更有效的疫苗。虽然在鉴定结核分枝杆菌（Mtb）抗原候选物方面取得了重大进展，但成功疫苗设计的一个重大障碍仍然是我们对记忆反应如何介导肺保护的理解不足。本提案的长期目标是确定在肺中诱导针对肺病原体（如结核分枝杆菌）的保护性记忆免疫的基本要求。对结核病的保护性回忆反应与产生干扰素（IFN）-γ的CD 4 + T细胞的出现有关，许多研究都集中在诱导这些细胞，希望改善疫苗接种。不幸的是，与BCG介导的相比，没有发生改善。因此，其他因素可能在保护性记忆中发挥作用，确定这些因素是什么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，在肺中，产生白介素-17的记忆细胞先于IFN-γ记忆细胞应答，并且在没有这些细胞的情况下，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产生细胞聚集在非炎症肺中。在用Mtb攻击时，肺驻留记忆细胞产生IL-17并触发趋化因子的局部表达（阶段1）。趋化因子梯度吸引来自淋巴池的IFN-γ记忆细胞（阶段2）。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）。缺乏有效的IL-17应答（阶段1）消除了接种疫苗的小鼠产生对Mtb攻击的保护性回忆免疫应答的能力（阶段2和3）。肺驻留的IL-17产生的CD 4+记忆细胞群体是由疫苗接种产生的，并且这些细胞是疫苗诱导的抗TB保护的关键组分，这一发现是完全新颖的。确定这些细胞在接种疫苗后在肺中持续存在和存活所需的特定因素至关重要。我们提出两个目标。在目的一中，将研究肺中产生IL-17的记忆细胞的存活和维持所需的因素。在目的二中，将确定细胞的位置和影响该群体在肺中建立的因素。这项工作与公共卫生的相关性在于，它将促进疫苗战略的合理发展，因此有可能减少结核病的发病率。

DESCRIPTION (provided by applicant): 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.