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

7.项目摘要/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。了解其免疫致病机制对 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，激活的CD4+T辅助细胞 (Th)通过影响破骨细胞的形成，促进牙槽骨的破坏。目前尚不清楚的是 粘膜抗原提呈细胞在CD_4~+T细胞启动和可塑性中的作用 遭遇Keystone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，使个人易患牙周炎。我们目前的情况 目的：研究牙周Th17和iTreg细胞分化和可塑性的动力学。 牙龈卟啉单胞菌(PG)口腔定植后受朗格汉斯细胞(LCS)调节。我们有 初步数据表明，LCS的缺失不会改变活化的CD4+T细胞的克隆性扩增 但阻止Pg牙痛毒力因子特异性的Th17细胞的分化。我们假设 PG持续口腔定植诱导黏膜抗原提呈细胞(即LC)分化 有利于牙周Th17细胞在发育后期重新编程为表达Th细胞和iTregs的干扰素-γ 转化为表达IL-17A或干扰素-γ的细胞。为了验证我们的假设，我们将首先确定Th17和Th17的动力学 ITreg经口给药后小鼠牙周组织中干扰素-γ−或IL-17A表达细胞的转化 接种PG。第二，确定口服LCS在促进Th17和iTreg可塑性方面的作用 用PG进行殖民。据我们所知，我们是世界上第一个设计出i- 展示PG天然表位的AB四聚体，将用于追踪PG特异的CD4+T细胞 LCS的靶向消融。我们的策略使用了报告鼠品系的基因杂交，明确地说 并永久标志着Th17和iTregs的发展命运。我们期望确定LCS的角色为 牙周组织中PG特异性Th17和iTreg细胞的晚期发育重新编程的调节 颈淋巴结节。随着对牙周病发病机制的深入了解， 通过治疗干预来操纵关键步骤并减轻或预防的机会 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.