Impact of mucosal immunization on generation of protective lung-resident IL-17 pr

描述(申请人提供)：结核病(TB)，由有机体结核分枝杆菌(Mtb)引起，每年在全球范围内导致200多万人死亡。我们对疫苗反应如何调节肺部保护的有限理解仍然是成功设计结核病疫苗的主要障碍。传统上，对结核病的保护性免疫反应与产生细胞因子干扰素-γ(干扰素-α)的CD4+T辅助细胞的出现有关，并激活巨噬细胞控制结核分枝杆菌。我们最近发现，除了干扰素-？产生人群是疫苗诱导的第二群CD4+T辅助细胞，产生细胞因子IL-17，是预防结核病的关键。用Mtb 6 kDa早期分泌抗原蛋白(ESAT-61-20)中明确的免疫优势IAB限制性多肽(ESAT-61-20)在佐剂中皮下免疫小鼠，诱导产生抗原特异性干扰素？和白介素17的记忆细胞群。然而，只有产生IL-17的细胞存在于肺中，而产生干扰素的细胞在次级淋巴器官中被发现。当接触结核杆菌时，驻留在肺内的记忆细胞产生IL-17，并在肺内触发局部趋化因子的表达。这种趋化因子的梯度会从循环中吸引保护性的产生干扰素的记忆细胞。产生干扰素的记忆细胞到达肺并产生干扰素？然后激活巨噬细胞以阻止结核杆菌的生长。重要的是，在没有IL-17召回反应的情况下，加速的干扰素？内存响应不发生，保护丢失。开发新的结核病疫苗的大多数方法都集中在抗原皮下传递途径上。然而，最近，与其他免疫途径相比，粘膜免疫被证明在受到强毒结核分枝杆菌的攻击时具有更好的保护作用。这与在粘膜部位免疫可产生对粘膜传染病的卓越保护作用的假设相一致。然而，通过呼吸道粘膜免疫来增强对结核病的保护的免疫机制仍未被探索。大多数使用粘膜免疫对抗结核分枝杆菌的研究都研究了干扰素的产生。反应作为免疫激活的读数。然而，我们最近发现，皮下免疫产生的产生IL-17的记忆细胞是疫苗诱导的抗结核病保护的关键组成部分，这让我们提出了几个关于粘膜免疫诱导IL-17反应的基本问题。在第一个目标中，我们将确定黏膜免疫是否产生保护性的驻肺的产生IL-17的记忆细胞，以及改变佐剂和包括粘膜辅助佐剂是否会产生更有效的IL-17记忆反应。在第二个目标中，我们将确定启动T细胞群的抗原提呈细胞的特征，并确定粘膜免疫后T细胞启动的诱导部位。当前提案的目的将促进粘膜疫苗策略的合理发展，长期目标是改进针对结核分枝杆菌的免疫策略。 由结核分枝杆菌(Mtb)引起的结核病每年导致全球200多万人死亡，成功的结核病疫苗设计的主要障碍是我们对肺部对结核病的早期记忆反应的要求缺乏了解。改善结核病免疫策略的必要性使我们了解在肺部诱导针对结核病的长期有效免疫的基本要求是重要的。这项工作与公共卫生的相关性在于，它将促进粘膜疫苗战略的合理发展，因此有可能降低结核病的发病率。

DESCRIPTION (provided by applicant): Tuberculosis(TB), caused by the organism M. tuberculosis (Mtb) kills more than 2 million people worldwide every year. Our limited understanding of how vaccine responses mediates protection in the lung remains a major hurdle to successful vaccine design against TB. The protective immune response to TB has conventionally been associated with the appearance of CD4+ T helper cells that produce the cytokine interferon gamma (IFN-?), and activates macrophages to control Mtb. We have recently identified that in addition to the IFN-? producing population, a second population of vaccine-induced CD4+ T helper cells that - produce the cytokine interleukin (IL)-17, is key for protection against TB. Subcutaneous immunization of mice with a defined immunodominant IAb-restricted peptide from the Mtb 6kDa Early Secretory Antigenic Protein (ESAT-61-20) in an adjuvant induces both antigen-specific IFN-?-producing and IL-17-producing memory cell populations. However, only the IL-17-producing cells populate the lung while the IFN-?-producing cells are found in the secondary lymphoid organs. The lung-resident memory cells upon exposure to Mtb, produce IL-17 and trigger local expression of chemokines in the lung. This chemokine gradient then attracts protective IFN-?- producing memory cells from the circulation. The arrival of the IFN-?-producing memory cells in the lung and production of IFN? then activates macrophages to halt Mtb growth. Importantly, in the absence of the IL-17 recall response, the accelerated IFN-? memory response does not occur and protection is lost. A majority of approaches to the development of new TB vaccines have focused on subcutaneous route of antigen delivery. However more recently, mucosal immunization has been shown to be more protective upon challenge with virulent Mtb than other routes of immunization. This is consistent with the hypothesis that immunization at the mucosal sites generates superior protection against mucosal infectious diseases. However, the immune mechanisms underlying enhanced protection by respiratory mucosal immunization against TB remains unexplored. Most studies that have used mucosal immunization against Mtb have studied the generation of IFN? responses as a readout of immune activation. However, our recent discovery that IL-17-producing memory cells generated by subcutaneous immunization are a critical component of vaccine-induced protection against TB leads us to raise several basic questions about the induction of IL-17 responses by mucosal immunizations. In Aim One, we will determine whether mucosal immunization generates protective lung- resident IL-17-producing memory cells and whether altering the adjuvant and including mucosal coadjuvants will generate more effective IL-17 memory responses. In Aim Two, we will characterize the antigen presenting cells that prime T cell populations and we will define the inductive sites of T cell priming following mucosal immunization. The aims of the current proposal will promote rational development of mucosal vaccine strategies with the long term goal of improving immunization strategies against Mtb. Tuberculosis(TB), caused by the organism M. tuberculosis (Mtb) kills more than 2 million people worldwide every year, the major hurdle to successful vaccine design against TB is our poor understanding of the requirements for early memory responses to TB in the lung. The need to improve immunization strategies against TB makes it important for us to understand the basic requirements for induction of long-lived effective immunity in the lung against TB. The relevance of this work to public health is that it will promote rational development of mucosal vaccine strategies and will therefore have the potential to reduce the incidence of TB.