T cell memory to TB in the lung

描述(申请人提供)：结核病(TB)是一个严重的公共卫生问题，合理开发有效的疫苗需要我们了解调节保护性免疫的细胞机制；这是当前提案的重点。我们在这里表明，尽管保护性记忆可以有效地对抗结核分枝杆菌(Mtb)，但当挑战途径模拟自然暴露时，保护性记忆会被延迟。至关重要的是，这种延迟允许细菌在肺部生长，即使是接种疫苗的小鼠也是如此。显然，加速记忆反应以更早地抑制细菌生长是一个重要的目标。在这方面，我们已经确定了一种新的记忆细胞群体，它产生白介素17，驻留在肺中，对气溶胶感染快速反应，这是保护记忆所必需的。在缺乏这种IL-17记忆群体的情况下，干扰素-？记忆响应丢失。产生IL-17的记忆细胞依赖于IL-23，并与加速的趋化因子反应有关。这些数据提出了一种假设，即产生IL-17的记忆细胞会招募干扰素？生产存储单元。如果这是真的，那么产生IL-17的记忆群体是疫苗接种的新的主要目标。具体地说，操纵这些细胞的反应可以克服保护记忆的延迟，这种延迟限制了当前疫苗策略的效力。在这个方案中，我们将测试以下工作模型：疫苗诱导的、IL-23依赖的、产生IL-17的记忆CD4+T细胞驻留在肺对结核分枝杆菌做出反应，产生IL-17，触发局部表达的趋化因子，吸引产生干扰素的记忆CD4+T细胞。这些干扰素-？记忆的CD4+T细胞然后激活髓系细胞以阻止结核分枝杆菌的生长。该模型将通过三个目标进行测试：目标一：确定诱导保护性记忆T细胞所需的因素。将确定IL-23在能够填充肺的产生IL-17的记忆细胞的增殖、存活和表型发展中的需求。目的二：确定IL-17是否通过募集干扰素-1介导疫苗诱导的保护作用。产生CD4+T细胞。我们将确定IL-17诱导的趋化因子反应和产生干扰素的记忆细胞的加速积累是否是疫苗诱导保护所必需的。目的三：确定调节肺内IL-17记忆反应是否能增强保护作用。我们将确定增加肺中IL-17的数量是否会改善疫苗诱导的保护作用。这一工作模型的证明将为合理的疫苗设计和研究这些细胞在人类中的作用提供基础。 与公共卫生相关：我们对疫苗诱导的结核病保护性反应如何发挥作用知之甚少。如果我们不知道反应是如何起作用的，就很难改进它。通过研究这种反应的工作方式，我们已经确定了可以作为疫苗靶点的新细胞类型。这些新的细胞类型可能会提高疫苗的保护效果，从而降低世界上的结核病发病率。这将对全球公共卫生产生重大影响。

DESCRIPTION (provided by applicant): Tuberculosis (TB) is a serious public health issue and rational development of effective vaccines requires that we understand the cellular mechanisms mediating protective immunity; this is the focus of the current proposal. We show here that while protective memory can be effective against Mycobacterium tuberculosis (Mtb) it is delayed when the challenge route mimics natural exposure. Crucially, this delay allows bacterial growth in the lungs even of vaccinated mice. Clearly, accelerating the memory response to result in earlier suppression of bacterial growth is an important goal. In this regard we have identified a novel population of memory cells that produces interleukin (IL)-17, resides in the lung, responds quickly to aerosol infection and which is required for protective memory. In the absence of this IL-17 memory population, the interferon (IFN)-? memory response is lost. The IL-17-producing memory cells are IL-23 dependent and are associated with an accelerated chemokine response. These data prompted the hypothesis that IL-17-producing memory cells recruit IFN-? producing memory cells. If this is true then the IL-17-producing memory population is a novel prime target for vaccination. Specifically, manipulating the response of these cells could overcome the delay in the protective memory that limits the efficacy of current vaccine strategies. In this proposal we will test the following working model: Vaccine-induced, IL-23 dependent, IL-17-producing memory CD4+ T cells resident in the lung respond to Mtb, produce IL-17, trigger the local expression of chemokines which attract IFN-?-producing memory CD4+ T cells. These IFN-? memory CD4+ T cells then activate myeloid cells to halt Mtb growth. The model will be tested using three aims: Aim One: To determine the factors required for induction of protective memory T cells. The requirement for IL-23 in proliferation, survival and phenotypic development of IL-17-producing memory cells capable of populating the lung will be determined. Aim Two: To determine whether IL-17 mediates vaccine-induced protection by recruiting IFN-? producing CD4+ T cells. We will determine whether IL-17-induced chemokine responses and accelerated accumulation of IFN-?-producing memory cells are essential for vaccine-induced protection. Aim Three: To determine whether modulating the IL-17 memory response in the lung can increase protection. We will determine whether increasing the IL-17 population in the lung improves vaccine-induced protection. Proof of this working model will provide a basis for rational vaccine design and investigation of the role of these cells in humans. PUBLIC HEALTH RELEVANCE: We know too little about how the vaccine-induced protective response to tuberculosis works. If we do not know how the response works it is difficult to improve upon it. By investigating the way the response works we have identified new cell types that can be targeted by vaccination. These new cell types may improve the protective effect of vaccines and thereby reduce the incidence of tuberculosis in the world. This will have a significant impact in worldwide public health.