REGULATING ANTIGEN PRESENTATION BY HUMAN FEMALE REPRODUCTIVE TRACT CELLS

女性生殖道（FRT）是一个独特的系统，必须 保护免受病原体感染，但也必须接受同种异体 精子和孕体。因此，与外周血不同， 与之对应，FRT内的免疫细胞受到性激素的影响 以符合这些双重功能的方式。我们的研究在这两个 人类和老鼠已经证明，性激素对 通过FRT抗原呈递细胞（APC）活化T细胞，并提供免疫调节。 目前提案的基础，旨在测试 假设免疫系统的诱导臂是免疫系统的诱导臂， 在人类FRT中调节。要解决的问题是：（1）可以 人FRT上皮细胞呈递抗原？(2)上皮细胞是如何- 白细胞相互作用调节T细胞活化？(3)仗着什么 内分泌平衡调节抗原提呈的机制？;和 (4)Fc受体靶向是否增强FRT细胞的抗原呈递？ 我们将分离出纯的上皮细胞群和专职APC 从每个FRT组织，并表征其抗原效率 对抗原应答的呈递（破伤风类毒素;确定的肽; 同种异体APC）和多克隆T细胞活化剂（抗CD 3;细菌 超抗原）。然后我们将确定上皮细胞和基质细胞 细胞群调节专职APC（巨噬细胞和树突状细胞） 表型、成熟和T细胞活化的效率，并将使用 阻断抗体和可溶性受体以评估细胞因子， 这些信号分子影响APC对T细胞的激活。我们还将 研究性激素和细胞因子，它们在怀孕期间是如何波动的。 月经周期，直接或间接改变APC的表型或功能， 通过对基质和上皮细胞群的影响。最后基于 观察到T细胞活化通过靶向 抗原的Fc受体，我们将确定FRT APC的IgG-和 IgA-受体靶向增强抗原呈递，以及 细胞因子和性激素对该途径的影响。 因此，这些研究将导致对身份的系统分析 和抗原呈递效率的APC群体天然存在于 每个不同的人类FRT组织部位。因此，我们将调查 机制，包括处理、介绍和提供共同 刺激信号和T细胞活化所必需的细胞因子，导致 了解性激素和细胞因子的作用， 或通过对附近细胞的影响，以增加或减少APC 功能总的来说，这些研究应该大大增加我们的 了解激素对诱导和/或抑制 免疫反应在这一关键器官系统，并奠定了基础， 制定切实可行的办法， 性传播疾病

The female reproductive tract (FRT) is a unique system that must be protected from infection by pathogens, yet must also accept allogeneic spermatozoa and conceptuses. Thus, unlike their peripheral blood counterparts, immune cells within the FRT are influenced by sex hormones in a manner consistent with these dual functions. Our studies in both the human and rat have demonstrated that sex hormones have profound effects on T cell activation by FRT antigen presenting cells (APC), and provide the foundation for the current proposal, which is designed to test the hypothesis that the inductive arm of the immune system is hormonally regulated within the human FRT. Questions to be addressed are: (1) Can human FRT epithelial cells present antigens?; (2) How do epithelial cell- leukocyte interactions modulate T cell activation?; (3) By what mechanism(s) does endocrine balance modulate antigen presentation?; and (4) Does Fc receptor targeting enhance antigen presentation by FRT cells? We will isolate pure populations of epithelial cells and professional APC from each FRT tissue and characterize their efficiency of antigen presentation in response to antigen (tetanus toxoid; defined peptides; allogeneic APC) and polyclonal T cell activators (anti-CD3; bacterial super-antigen). We will then determine how epithelial and stromal cell populations modulate professional APC (macrophages and dendritic cells) phenotype, maturation, and efficiency for T cell activation, and will use blocking antibodies and soluble receptors to evaluate the cytokines and signaling molecules that influence T cell activation by APC. We will also examine how sex hormones and cytokines, which fluctuate during the menstrual cycle, alter the phenotype or function of APC either directly or via effects on stromal and epithelial cell populations. Finally, based on observations that T cell activation is markedly enhanced by targeting antigen to Fc receptors, we will determine the FRT APC for which IgG- and IgA-receptor targeting enhances antigen presentation, as well as the effects of cytokines and sex hormones on this pathway. These studies will thus result in the systematic analysis of the identity and antigen presenting efficiency of APC populations naturally present at each of the different human FRT tissue sites. Thus, we will investigate mechanisms including processing, presentation, and provision of co- stimulatory signals and cytokines necessary for T cell activation, leading to an understanding of how sex hormones and cytokines act, either directly on APC or through effects on nearby cells, to increase or decrease APC function. Overall, these studies should significantly increase our knowledge about the hormonal influences on induction and/or suppression of immune responses in this critical organ system, and lay the foundation for developing realistic approaches to the development of vaccines for sexually transmitted diseases.