T cell memory to TB in the lung

描述（由申请人提供）：结核病（TB）是一个严重的公共卫生问题，有效疫苗的合理开发要求我们了解介导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，虽然保护性记忆可以有效对抗结核分枝杆菌（Mtb），但当挑战途径模仿自然暴露时，它会被延迟。至关重要的是，这种延迟甚至允许细菌在接种过疫苗的小鼠的肺部生长。显然，加速记忆反应以导致细菌生长的早期抑制是一个重要的目标。在这方面，我们已经确定了一种新的记忆细胞群，它产生白细胞介素(IL)-17，驻留在肺部，对气溶胶感染反应迅速，这是保护性记忆所必需的。在缺乏这种IL-17记忆群的情况下，干扰素(IFN)-？内存响应丢失。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。这些数据提示了产生il -17的记忆细胞招募IFN-？产生记忆细胞。如果这是真的，那么产生il -17的记忆群体是接种疫苗的一个新的主要目标。具体来说，控制这些细胞的反应可以克服限制当前疫苗策略有效性的保护性记忆延迟。在这个提议中，我们将测试以下工作模型：疫苗诱导的，依赖IL-23的，产生IL-17的记忆CD4+ T细胞驻留在肺中，对Mtb有反应，产生IL-17，触发局部趋化因子的表达，吸引IFN-？产生记忆性CD4+ T细胞。这些干扰素- ?记忆CD4+ T细胞然后激活骨髓细胞来阻止结核分枝杆菌的生长。该模型将使用三个目标进行测试：目标一：确定诱导保护性记忆T细胞所需的因素。IL-23在产生il -17记忆细胞的增殖、存活和表型发育中的需求将被确定。目的二：确定IL-17是否通过募集IFN-介导疫苗诱导的保护作用？产生CD4+ T细胞我们将确定il -17是否诱导趋化因子反应和IFN-？产生记忆细胞对于疫苗诱导的保护至关重要。目的三：确定调节IL-17在肺中的记忆反应是否可以增加保护作用。我们将确定增加肺中IL-17的数量是否能提高疫苗诱导的保护作用。这一工作模型的证明将为合理设计疫苗和研究这些细胞在人体中的作用提供基础。

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.