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

牙龈朗格汉斯细胞调节牙龈卟啉单胞菌特异性 T 细胞的可塑性

基本信息

批准号：
9165057
负责人：
MASSIMO COSTALONGA
金额：
$ 22.34万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9165057
关键词：
Ablation Adult Affect Antigen-Presenting Cells Antigens Automobile Driving CD4 Positive T Lymphocytes Cells Cervical lymph node group Characteristics Chronic Clonal Expansion Data Dental Development Disease Ecosystem Engineering Environment Epithelial Epithelium Epitopes Genetic Crosses Gingiva Goals Gram-Negative Bacteria Grant Helper-Inducer T-Lymphocyte Human Immune Immune response Individual Infection Inflammatory Interferon Type II Interleukin-17 Kinetics Knowledge Langerhans cell Lesion Leukocytes MHC Class II Genes Mediating Microbe Microbial Biofilms Modeling Molecular Mouse Strains Mus Oral Pathology Patients Periodontal Diseases Periodontitis Periodontium Phenotype Play Population Porphyromonas gingivalis Positioning Attribute Production Reagent Regulatory T-Lymphocyte Reporter Reporting Research Research Personnel Role Shapes Signal Transduction Staging Structure of gingival sulcus Submucosa Surface T-Lymphocyte Testing Therapeutic Intervention Time Tissues Tooth Loss Tooth structure United States Vaccines Virulence Factors Work alveolar bone bone cost cytokine gingipain in vivo lymph nodes microbial mouse model novel oral infection osteoclastogenesis pathogen prevent programs response targeted treatment tool unnecessary treatment

项目摘要

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.

7. 项目概要/摘要牙周炎是一种慢性炎症性疾病，影响着 30-40% 的美国人。了解牙周组织破坏和牙齿脱落的原因对于了解其免疫发病机制非常重要。开发细胞介导的疫苗因为我们无法准确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) 通过影响破骨细胞生成导致牙槽骨破坏。目前尚不清楚的是。粘膜抗原呈递细胞对 CD4+ T 细胞启动和可塑性的相对作用我们的长期目标是识别和表征其成分。对牙周病原体的局部免疫反应使个体易患牙周炎。目的是确定牙龈 Th17 和 iTreg 细胞的分化和可塑性动力学，即牙龈卟啉单胞菌 (Pg) 口腔定植后，由朗格汉斯细胞 (LC) 调节。初步数据表明，LC 的缺失不会改变激活的 CD4+ T 的克隆扩增细胞，但阻止对 Pg 牙龈蛋白酶毒力因子具有特异性的 Th17 细胞的分化。 Pg 的持续口服定植会诱导粘膜抗原呈递细胞（即 LC）差异化有利于牙龈 Th17 细胞在发育后期重编程为表达 IFN-γ 的 Th 细胞和 iTreg 为了检验我们的假设，我们将首先确定 Th17 和 IFN-γ 表达细胞的动力学。口服后小鼠牙龈中 iTreg 的持久性和转化为表达 IFN-γ− 或 IL-17A 的细胞其次，确定口服 LC 在口服后驱动 Th17 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- 的团队。 Ab 四聚体显示 Pg 的天然表位，将用于追踪 Pg 特异性 CD4+ T 细胞我们的策略采用了报告小鼠品系的基因杂交，这无疑是有针对性的。并永久标记 Th17 和 iTreg 的发育命运，我们希望确定 LC 的作用。牙龈或牙龈中 Pg 特异性 Th17 和 iTreg 细胞晚期发育重编程的调节因子随着对牙周病发生机制的深入了解，颈淋巴结也随之而来。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。