Cellular Immunity to Chlamydua at the Epithelial Interface

描述（由申请人提供）：沙眼衣原体具有明显的组织趋向性，几乎只在生殖道上皮细胞中复制。人类沙眼衣原体病小鼠模型清楚地表明T细胞介导对生殖道感染的保护性免疫。该基金的中心假设是负责使免疫绝育的衣原体特异性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细胞亚群从生殖道中消除受感染的上皮细胞，以及它们如何实现预期的终点。具体而言，该基金拟用于：1)鉴定与衣原体感染的输卵管上皮细胞相互作用介导绝育免疫的T细胞亚群，并确定其效应机制；2)确定上皮细胞用于呈递衣原体抗原的特异性抗原递呈途径；3)确定受感染上皮细胞对衣原体特异性保护性T细胞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，作为分离衣原体特异性T细胞系的抗原提呈细胞。了解T细胞如何与受感染的上皮细胞相互作用介导绝育免疫，可能有助于通过鉴定可在未来疫苗试验中利用的保护性免疫替代标记物来开发疫苗。自20世纪90年代初以来，生殖道沙眼衣原体感染一直是美国最常见的细菌性性病。在女性中，沙眼衣原体感染通常会上升到输卵管，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原体感染的发病率，因此开发衣原体疫苗将是公共卫生领域向前迈出的重要一步。这笔拨款旨在通过研究保护性免疫如何在生殖道中起作用，为衣原体疫苗的合理开发做出贡献。确定保护性T细胞是什么样子的，以及它们如何起作用，对于设计和评估未来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.