Cellular Immunity to Chlamydua at the Epithelial Interface

描述(申请人提供)：沙眼衣原体具有明显的组织嗜性，几乎只在生殖道衬里的上皮细胞中复制。沙眼衣原体沙眼衣原体感染的小鼠模型已经清楚地证明T细胞介导了对生殖道感染的保护性免疫。这项拨款的中心假设是，负责消毒免疫的衣原体特异性T细胞与受感染的生殖道上皮细胞相互作用。令人惊讶的是，人们对T细胞与衣原体感染的上皮细胞的相互作用知之甚少。该项目的主要目标是了解哪些衣原体特异性T细胞亚群消除了生殖道中受感染的上皮细胞，以及它们如何实现预期的终点。具体而言，该基金建议：1)确定与衣原体感染的输卵管上皮细胞相互作用的T细胞亚群，以介导灭菌免疫，并确定所采用的效应机制；2)确定上皮细胞用来呈递衣原体抗原的特定抗原提呈途径；3)确定受感染的上皮细胞对保护性衣原体特异性T细胞的激活的共刺激和共抑制作用。为了解决这些特定的目的，已经产生了独特的输卵管上皮细胞系作为抗原提呈细胞，用于分离衣原体特异性T细胞系。了解T细胞如何与受感染的上皮细胞相互作用以介导灭菌免疫，可能有助于通过识别保护性免疫的替代标记，在未来的疫苗试验中加以利用。自20世纪90年代初S以来，生殖道沙眼衣原体感染一直是美国最常见的细菌性性病。在妇女中，沙眼衣原体感染通常上升到输卵管，导致不孕和异位妊娠。标准的公共卫生措施并没有显著降低沙眼衣原体感染的发病率，因此，开发沙眼衣原体疫苗将是公共卫生向前迈出的重要一步。这笔赠款建议通过研究保护性免疫在生殖道中的作用，为合理开发衣原体疫苗做出贡献。确定保护性T细胞是什么样子，以及它们是如何发挥作用的，对于设计和评估未来的衣原体候选疫苗至关重要。

DESCRIPTION (provided by applicant): Chlamydia trachomatis has a marked tissue tropism, replicating almost exclusively in epithelial cells lining the reproductive tract. The Chlamydia muridarum mouse model for human C. trachomatis disease has clearly demonstrated that T cells mediate protective immunity against reproductive tract infection. The central hypothesis of the grant is that Chlamydia-specific T cells responsible for sterilizing immunity interact with infected reproductive tract epithelial cells. Surprising little is known about T cell interactions with Chlamydia-infected epithelial cells. The major goal of the project is to understand which Chlamydia-specific T cell subsets eliminate infected epithelial cells from the reproductive tract, and how they accomplish that desired endpoint. Specifically the grant proposes to 1) To identify T cell subsets that interact with Chlamydia-infected oviduct epithelial cells to mediate sterilizing immunity, and identify the effector mechanism employed, 2) To define the specific antigen presentation pathways utilized by epithelial cells to present the Chlamydia antigens, 3) To determine the costimulatory and coinhibitory contributions of infected epithelial cells to activation of protective Chlamydia-specific T cells. To address these specific aims, unique oviduct epithelial cell lines have been generated to serve as antigen presenting cells for isolating Chlamydia- specific T cell lines. Understanding how T cells interact with infected epithelial cells to mediate sterilizing immunity may contribute to vaccine development by identifying surrogate markers for protective immunity that can be exploited in future vaccine trials. Chlamydia trachomatis infections of the reproductive tract have been the most commonly diagnosed bacterial STD in the United States since the early 1990's. In women, C. trachomatis infections commonly ascend into the Fallopian tubes causing infertility and ectopic pregnancies. Standard public health measures have not significantly decreased the incidence of C. trachomatis infections, therefore development of a Chlamydia vaccine would be a major step forward in public health. This grant proposes to contribute toward rational development of a Chlamydia vaccine by investigating how protective immunity works in the reproductive tract. Defining what protective T cells look like, and how they function, will be critical for designing and assessing future Chlamydia candidate vaccines.