Gingival Langerhans cells regulate plasticity of P. gingivalis-specific T cells

7.项目概要/摘要 牙周炎是一种慢性炎症性疾病，影响30-40%的美国人口。它是领先的 牙周组织破坏和牙齿脱落的原因。了解其免疫发病机制对于 开发细胞介导的疫苗，因为我们不能准确地预测牙周炎的发展， 导致牙科患者接受不必要的治疗。已知的是，活化的CD 4 + T辅助细胞 (Th)通过影响破骨细胞的生成而导致牙槽骨的破坏。目前尚不清楚的是， 粘膜抗原呈递细胞对免疫后CD 4 + T细胞启动和可塑性的相对作用 遇到了一种关键病原体我们的长期目标是识别和表征 对牙周病原体的局部免疫反应，使个体易患牙周炎。我们目前 目的是确定牙龈Th 17和iTreg细胞的分化和可塑性的动力学， 在用牙龈卟啉单胞菌（Pg）口腔定殖后由朗格汉斯细胞（LC）调节。我们有 初步数据表明，LCs的缺乏不会改变活化的CD 4 + T细胞的克隆扩增， 细胞，但阻止了对Pg牙龈菌蛋白酶毒力因子特异性的Th 17细胞的分化。我们假设 Pg的持续口服定殖诱导粘膜抗原呈递细胞（即LC）差异表达， 有利于牙龈Th 17细胞晚期发育重编程为表达IFN-γ的Th细胞和iTh细胞 IL-17 A或IFN-γ表达细胞。为了检验我们的假设，我们将首先确定Th 17的动力学， 口服给药后小鼠牙龈中iTreg持续存在并转化为IFN-γ−或IL-17 A表达细胞 其次，确定口服LC在口服后驱动Th 17和iTreg可塑性中的作用。 据我们所知，我们是世界上第一个设计出I- 展示来自Pg的天然表位的Ab四聚体，其将用于在免疫后追踪Pg特异性CD 4 + T细胞。 LC的靶向消融。我们的策略采用遗传杂交的小鼠品系， 并永久地标记Th 17和iT 3的发育命运。我们希望确定LC的作用， 牙龈中Pg特异性Th 17和iTreg细胞的晚期发育重编程的调节剂， 颈部淋巴结随着对引发牙周病的机制的深入了解， 通过治疗性干预措施来控制关键步骤， 牙周炎

7. PROJECT SUMMARY / ABSTRACT Periodontitis is a chronic inflammatory disease that affects 30-40% of the U.S. population. It is the leading cause of periodontal tissue destruction and tooth loss. Understanding its immunopathogenesis is important for developing cell-mediated vaccines and because we cannot accurately predict the development of periodontitis, leading dental patients to undergo unnecessary treatment. What is known is that activated CD4+ T helper cells (Th) contribute to alveolar bone destruction by influencing osteoclastogenesis. What remains unknown is the relative roles of mucosal antigen presenting cells on the priming and plasticity of CD4+ T cells after encountering a keystone pathogen. Our long-range goal is to identify and characterize the components of the local immune response to periodontal pathogens that predisposes an individual to periodontitis. Our current objective is to determine the kinetics of differentiation and plasticity of gingival Th17 and iTreg cells that is modulated by Langerhans cells (LCs) after oral colonization with Porphyromonas gingivalis (Pg). We have preliminary data that suggests that absence of LCs does not alter the clonal expansion of activated CD4+ T cells but prevents the differentiation of Th17 cells specific for Pg gingipain virulence factors. We hypothesize that persistent oral colonization with Pg induces mucosal antigen presenting cells (i.e. LCs) to differentially favor the late developmental re-programming of gingival Th17 cells into IFN-γ expressing Th cells and iTregs into IL-17A- or IFN-γ-expressing cells. To test our hypothesis, we will first determine the kinetics of Th17 and iTreg persistence and conversion to IFN-γ− or IL-17A-expressing cells in the gingiva of mice following oral inoculation with Pg. Second, determine the role of oral LCs in driving Th17 and iTreg plasticity following oral colonization with Pg. To the best of our knowledge, we are the first group in the world to have engineered an I- Ab tetramer displaying native epitopes from Pg, which will be used to track Pg-specific CD4+ T cells after targeted ablation of LCs. Our strategy employs genetic crossing of reporter-mouse strains that unequivocally and permanently mark the developmental fate of Th17 and iTregs. We expect to determine the role of LCs as regulators of the late developmental re-programming of Pg-specific Th17 and iTreg cells either in the gingiva or cervical lymph nodes. With a deeper understanding of the mechanisms initiating periodontal disease comes opportunities through therapeutic interventions to manipulate key steps and mitigate against or prevent periodontitis.