Cervical T Cell Immunity to C. trachomatis

沙眼衣原体是最常见的性传播细菌感染。慢性沙眼衣原体疾病的破坏性生殖后果和易受艾滋病毒感染，使得制定有效的疫苗接种战略势在必行。然而，几个关键领域的有限信息严重阻碍了这一领域的进展。动物模型表明，T细胞反应是宿主抵抗的核心，但不能复制人类疾病的所有关键特征。沙眼衣原体是一种专性细胞内病原体，主要感染女性宫颈柱状上皮细胞，但很少感染。 已知的这些组织中局部免疫的诱导期或效应期。粘膜部位的免疫细胞在表型和功能上与循环中的免疫细胞不同，越来越明显的是，局部环境在调节局部免疫方面发挥着重要作用。然而，到目前为止，几乎所有的人类研究都集中在循环中沙眼衣原体的特异性免疫上，因为到目前为止，分离宫颈内淋巴样细胞遇到了很大的困难。在这里，这些问题将逐一得到解决。这一应用的主要焦点是表征人内膜沙眼衣原体感染主要部位的T细胞免疫反应，其基本假设是这些亚群的活动而不是循环T细胞最准确地反映了对这种病原体的关键宿主反应。最初，局部免疫环境将使用沙眼衣原体感染妇女抗生素治疗前和治疗后以及未感染对照组的分泌物和细胞刷状细胞样本来表征。 与循环T细胞群体的比较将澄清粘膜T细胞谱系的独特特征。下一步，宫颈内和循环中沙眼衣原体特异性的CD4和CD8T细胞的频率、细胞因子表达谱和裂解活性将直接在体外和在克隆细胞群中得到更密切的定义。最后，在我们的T细胞克隆研究中，将使用永生化的宫颈柱状上皮细胞来表征沙眼衣原体抗原的加工和呈递，这些细胞经过遗传或生化操作，直接抑制特定的宫颈内转运途径。这项研究设计将澄清沙眼衣原体与宫颈免疫系统之间的相互作用，这最终将大大有助于描述针对沙眼衣原体的保护性免疫反应，并开发有效的疫苗。

Chlamydia trachomatis is the most prevalent sexually transmitted bacterial infection. Devastating reproductive consequences of chronic C. trachomatis disease and a predisposition to HIV infection make progress towards the development of effective vaccination strategies imperative. However, limited information in several key areas has severely hampered progress in this area. Animal models have shown that T cell responses are central to host resistance but do not reproduce all the critical features of human disease. C. trachomatis is an obligate intracellular pathogen that primarily infects columnar epithelial cells of the endocervix in women, yet little is known either of the inductive or effector phases of local immunity in these tissues. Immune cells at mucosal sites are phenotypically and functionally distinct from their counterparts in the circulation and it is increasingly clear that the local milieu plays an important role in regulating local immunity. Nevertheless, almost all human studies to date have focused, perhaps inappropriately, on C. trachomatis-specific immunity in the circulation, since great difficulties have, to date, attended isolation of endocervical lymphoid ceils. Here, each of these issues will be addressed. The primary focus of this application is to characterize T cell immune responses at the primary site of C. trachomatis infection in the human endocervix with the underlying hypothesis that activity of these subpopulations, rather than circulating T cells, most accurately reflects the critical host response against this pathogen. Initially, the local immune milieu will be characterized using secretions and cytobrush cell specimens from C. trachomatis-infected women both pre-and post-antibiotic treatment and from uninfected controls. Comparisons with circulating T cell populations will clarify unique features of the mucosal T cell repertoire. Next, the frequencies, cytokine expression profiles and lytic activities of endocervical and circulating C. trachomatis-specific CD4 and CD8 T cells both will be more closely defined both directly ex vivo and in cloned cell populations. Finally, in studies with our T cell clones, processing and presentation of C. trachomatis antigens will be characterized, using immortalized endocervical columnar epithelial cells that are genetically or biochemically manipulated for directed inhibition of specific intraceUular trafficking pathways. This study design will clarify interactions between C. trachomatis and the cervical immune system that will ultimately aid greatly in delineating protective immune responses against C. trachomatis and the development of effective vaccines.