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

项目摘要：全球每年有200多万人死于结核病。唯一的结核病 疫苗可用，卡介苗(BCG)具有不同的疗效，这促使人们寻找 更有效的疫苗。虽然在分枝杆菌鉴定方面取得了重大进展 结核(结核分枝杆菌)候选抗原，成功疫苗设计的一个重大障碍仍然是我们的贫穷 了解记忆反应如何调节肺部的保护。这样做的长期目标是 建议定义在肺内诱导保护性记忆免疫的基本要求 结核分枝杆菌等肺部病原体。对结核病的保护性回忆反应与外表有关 产生干扰素-γ的CD4+T细胞，许多研究都集中在诱导这些细胞在 希望提高疫苗接种率。不幸的是，与BCG调解的情况相比，情况并未得到改善。它是 因此，其他因素可能在保护记忆中发挥作用，并决定这些因素是什么 以及如何对它们进行调节将导致疫苗效力的大幅提高。在这方面， 我们最近发现，产生白细胞介素17的记忆细胞先于干扰素-Y记忆细胞 在没有这些细胞的情况下，干扰素-v记忆反应不会发生。 基于初步数据，我们提出了结核病疫苗诱导保护的三阶段模型。首先， 接种疫苗可同时诱导产生干扰素-γ和白介素17的细胞，但只有产生白介素17的细胞出现在非炎症状态 阿龙。当受到结核分枝杆菌的攻击时，肺常驻记忆细胞产生IL-17并触发局部 趋化因子的表达(阶段1)。趋化因子梯度吸引淋巴组织中的干扰素-γ记忆细胞 泳池(第二期)。反过来，这些干扰素-γ细胞激活肺中的髓细胞以阻止结核分枝杆菌的生长(阶段3)。这个 缺乏有效的IL-17反应(阶段1)会削弱接种疫苗的小鼠产生 对结核分枝杆菌挑战的保护性召回免疫反应(阶段2和3)。研究发现，一种驻留在肺部的IL-17- 产生CD4+记忆细胞的群体是通过接种疫苗产生的，这些细胞是关键 疫苗诱导的预防结核病的成分是完全新的。确定特定的影响因素 这些细胞在接种疫苗后在肺内的持久性和存活率至关重要。我们 提出两个目标。目的一：IL-17产生细胞生存和维持所需的因素 将对肺中的记忆细胞进行研究。在目标二中，细胞的位置和影响因素 这一人口在肺中的建立将被确定。这项工作与公共卫生的相关性 是它将促进疫苗战略的合理发展，因此将有可能 降低结核病发病率。

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.