Cervical T Cell Immunity to C. trachomatis

沙眼衣原体是最常见的性传播细菌感染。慢性丙型肝炎的毁灭性生殖后果。沙眼疾病和艾滋病毒感染的易感性使得必须在制定有效的疫苗接种战略方面取得进展。然而，几个关键领域的信息有限，严重阻碍了这一领域的进展。动物模型已经表明，T细胞反应是宿主抵抗力的核心，但不能复制人类疾病的所有关键特征。C.沙眼是一种专性细胞内病原体，主要感染妇女宫颈内膜的柱状上皮细胞， 已知这些组织中局部免疫的诱导或效应阶段。粘膜部位的免疫细胞在表型和功能上与循环中的对应物不同，并且越来越清楚的是，局部环境在调节局部免疫中起重要作用。尽管如此，迄今为止几乎所有的人类研究都集中在C。循环中的沙眼特异性免疫，因为迄今为止，分离颈内淋巴细胞有很大的困难。在此，将逐一讨论这些问题。本申请的主要焦点是表征在C.在人宫颈内膜沙眼感染的基础假设，这些亚群的活性，而不是循环T细胞，最准确地反映了关键的主机对这种病原体的反应。最初，局部免疫环境将使用来自C的分泌物和细胞刷细胞标本来表征。沙眼感染的妇女在抗生素治疗前后和未感染的对照组。 与循环T细胞群的比较将阐明粘膜T细胞库的独特特征。其次，研究了宫颈内和循环中C.沙眼特异性CD4和CD8 T细胞都将在直接离体和克隆细胞群中更精确地定义。最后，在我们的T细胞克隆的研究中，C.将使用永生化的宫颈内柱状上皮细胞来表征沙眼衣原体抗原，所述细胞被遗传或生物化学操纵以定向抑制特异性细胞内运输途径。本研究设计将阐明C.沙眼衣原体和宫颈免疫系统，这将最终大大有助于描绘针对C.沙眼和开发有效的疫苗。

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.