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

描述（由申请人提供）：结核病（TB），由结核分枝杆菌（Mtb）引起，每年在全球造成200多万人死亡。我们对疫苗反应如何介导肺部保护的理解有限，这仍然是成功设计结核病疫苗的主要障碍。对结核病的保护性免疫反应通常与CD4+ T辅助细胞的出现有关，这些细胞产生细胞因子干扰素γ (IFN- γ)，并激活巨噬细胞来控制结核分枝杆菌。我们最近发现，除了IFN-？产生细胞群是疫苗诱导的CD4+ T辅助细胞的第二种细胞群，它们产生细胞因子白细胞介素(IL)-17，是预防结核病的关键。用佐剂中的Mtb 6kDa早期分泌抗原蛋白（ESAT-61-20）确定的免疫优势抗体限制性肽对小鼠进行皮下免疫，可诱导抗原特异性IFN-？产生il -17和il -17的记忆细胞群。然而，只有产生il -17的细胞填充肺部，而IFN-？-产生细胞见于次级淋巴器官。暴露于Mtb后，肺驻留记忆细胞产生IL-17并触发肺内趋化因子的局部表达。趋化因子梯度然后吸引保护性IFN-？-从循环中产生记忆细胞。IFN-？-在肺中产生记忆细胞和产生IFN？然后激活巨噬细胞来阻止结核分枝杆菌的生长。重要的是，在缺乏IL-17回忆反应的情况下，IFN-？记忆反应没有发生，保护也就失去了。开发新结核疫苗的大多数方法都集中在皮下递送抗原的途径上。然而，最近，粘膜免疫已被证明对强毒性结核杆菌的攻击比其他免疫途径更具保护作用。这与在粘膜部位免疫产生对粘膜传染病的优越保护的假设是一致的。然而，呼吸道粘膜免疫对结核病增强保护的免疫机制仍未被探索。大多数使用粘膜免疫对抗Mtb的研究都研究了IFN的产生。反应作为免疫激活的读数。然而，我们最近发现，由皮下免疫产生的产生IL-17的记忆细胞是疫苗诱导的结核病保护的关键组成部分，这使我们对粘膜免疫诱导IL-17反应提出了几个基本问题。在Aim One中，我们将确定粘膜免疫是否产生保护性的肺驻留IL-17产生记忆细胞，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。在目标二中，我们将描述启动T细胞群的抗原呈递细胞，并定义粘膜免疫后T细胞启动的诱导位点。本建议的目的是促进黏膜疫苗策略的合理发展，长期目标是改善针对结核分枝杆菌的免疫策略。

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.