Regulation and Function of Oral Resident Memory T Cells

口腔驻留记忆 T 细胞的调节和功能

• 批准号: 10896496
• 负责人: James Michael Stolley
• 金额: $ 24.9万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10896496
• 关键词: Acceleration; Address; Allergic Disease; Animal Model; Antibiotics; Antibodies; Antigens; Aphthous Stomatitis; Architecture; Autoantigens; Autoimmune; Autoimmune Diseases; Autoimmunity; Bacteria; Biology; Blood; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell physiology; Cells; Cellular biology; Chemicals; Choristoma; Chronic; Circulation; Communicable Diseases; Dental Hygiene; Disease; Environment; Event; Foundations; Gene Expression; Generations; Gingiva; Goals; Growth; Homeostasis; Human; Human Papillomavirus; Immune; Immune System Diseases; Immune response; Immunity; Immunologic Surveillance; Immunologics; Immunologist; Immunology; Individual; Infection; Inflammation; Inflammatory; Intercept; Invaded; Knockout Mice; Knowledge; Ligature; Location; Lung; Maintenance; Malignant Neoplasms; Mediating; Mediator; Memory; Microscopy; Molecular; Mouth Diseases; Mucous Membrane; Mus; Operative Surgical Procedures; Oral; Oral Lichen Planus; Oral cavity; Oral health; Oral mucous membrane structure; Organ; Parabiosis; Pathogenesis; Pathogenicity; Pathway interactions; Peptides; Periodontal Diseases; Periodontitis; Phase; Phenotype; Play; Population; Predisposition; Production; Property; Proteins; Regulation; Research Personnel; Resources; Role; Saliva; Salivary Glands; Severities; Shapes; Signal Transduction; Simplexvirus; Site; Skin; Solid; Specificity; T memory cell; T-Lymphocyte; Testing; Therapeutic; Therapeutic Intervention; Tissues; Training; Transforming Growth Factor beta; Tumor Antigens; Vaccination; Virulence; Virus Diseases; Work; antimicrobial; antiviral immunity; career; career development; clinically relevant; dietary; experimental study; immunopathology; improved; inhibitor; innovation; insight; malignant mouth neoplasm; microbial; microbial community; migration; mouse model; mucosal site; novel; novel therapeutic intervention; novel therapeutics; oral cavity epithelium; oral infection; oral microbiome; oral tissue; pathogen; pathogenic bacteria; pathogenic fungus; pathogenic virus; prevent; recruit; residence; secondary lymphoid organ; tissue resident memory T cell; translational potential; tumor; urogenital tract

Project Summary/Abstract Memory T cells chronicle an individual’s infectious past and afford protection to reinfection. Historically defined in blood and subdivided based on their ability to access secondary lymphoid organs, an additional mechanism of T cell immunosurveillance has more recently been described. Here, memory T cells forgo systemic recirculation in exchange for durable residence in non-lymphoid tissues (NLT). Such tissue resident memory T cell (TRM) provide a mechanism for stockpiling immunity within specific barrier compartments commonly exploited by pathogens as portals of entry into the body. TRM function by rapidly intercepting invading pathogens and orchestrating collaborative immune responses. Within NLT, T cell immunosurveillance is predominated by TRM where they accelerate protection against reinfection, may be associated with tumor control, and may also facilitate the persistence of certain allergic and autoimmune diseases. These observations have bolstered TRM as major targets for vaccination. The therapeutic manipulation of TRM holds tremendous promise for the treatment of organ-specific immunological disorders, autoimmunity, and solid cancers. While extensively studied in other mucosal sites, there is presently a fundamental void in our understanding of the ontogeny, function, and therapeutic implications of oral-mucosal TRM. Considered amongst the most architecturally and biologically varied tissue sites in the body, the mouth is continuously bombarded by myriad dietary and environmental antigens and harbors diverse microbial communities. Moreover, the mouth and salivary glands can be colonized by bacterial, fungal, and viral pathogens including herpes simplex virus and human papilloma virus. Given their well- documented and critical functions in mediating barrier immunosurveillance in other NLT, oral TRM are likely to play a major role in antiviral immunity and oral immune homeostasis. TRM may also perpetuate chronic immune responses observed in periodontal disease and oral lichen planus. However, addressing their role in these clinically relevant settings has suffered from a lack of animal models which would facilitate the generation of sufficient oral TRM to manipulate and study. I have bridged this gap by developing a novel oral ‘prime-pull’ strategy, the first of its kind, for generating large quantities of tractable TRM in the oral mucosa. Leveraging this innovative approach, I will address outstanding fundamental questions regarding oral TRM biology with translational potential for human oral health. During the K99 phase, I will define the recruitment and retention signals governing oral TRM with implications for depleting pathogenic subsets (Aim 1). Experiments spanning the K99/R00 phases will investigate the consequences of oral TRM reactivation in shaping the microbial and inflammatory landscape of the mouth with clinical relevance for recrudescent oral infections and oral cancer (Aim 2). Work conducted in the R00 phase will define the role of oral TRM in the pathogenesis of periodontitis, the most common chronic inflammatory condition worldwide (Aim 3). In summary, work outlined in the proposal will pave a path forward towards my goal of developing therapeutic interventions targeting oral TRM.

项目总结/摘要 记忆T细胞记录了一个人的感染历史，并为再感染提供保护。历史定义 在血液中，并根据其进入次级淋巴器官的能力细分， T细胞的免疫监视最近被描述。在这里，记忆T细胞放弃了系统性的 再循环以换取在非淋巴组织（NLT）中的持久驻留。这种组织驻留存储器T 细胞（TRM）提供了一种在通常利用的特定屏障隔室中储存免疫力的机制 被病原体当作进入身体的入口TRM通过快速拦截入侵的病原体发挥作用， 协调协同免疫反应。在NLT中，T细胞免疫监视主要由TRM控制 在那里它们加速了对再感染的保护，可能与肿瘤控制有关，并且还可能 促进某些过敏性和自身免疫性疾病的持续存在。这些观察结果支持了TRM 作为疫苗接种的主要目标。TRM的治疗操作为治疗带来了巨大的希望 器官特异性免疫紊乱、自身免疫和实体癌。虽然在其他领域进行了广泛的研究， 粘膜部位，目前在我们对个体发育，功能和 口腔粘膜TRM的治疗意义。被认为是最具建筑和生物多样性的 作为身体的组织部位，口腔不断受到无数饮食和环境抗原的轰击， 拥有多种微生物群落。此外，口腔和唾液腺可以被细菌， 真菌和病毒病原体，包括单纯疱疹病毒和人乳头瘤病毒。鉴于他们的良好- 在其他NLT中，口服TRM在介导屏障免疫监视方面的记录和关键功能可能 在抗病毒免疫和口服免疫稳态中起主要作用。TRM也可能使慢性免疫性 在牙周病和口腔扁平苔藓中观察到的反应。然而，解决他们在这些方面的作用， 临床相关的设置遭受缺乏动物模型，这将有助于产生 足够的口腔TRM进行操作和研究。我已经通过开发一种新颖的口头'启动拉'来弥合这一差距 这是第一种在口腔粘膜中产生大量易处理的TRM的策略。利用这一 创新的方法，我将解决有关口腔TRM生物学悬而未决的基本问题， 人类口腔健康的转化潜力。在K99阶段，我将定义招聘和保留 控制口腔TRM的信号，暗示着消耗致病性亚群（目的1）。实验跨越 K99/R 00阶段将研究口服TRM再活化在形成微生物和 口腔炎性景观与复发性口腔感染和口腔癌的临床相关性（目的 2）的情况。在R 00阶段进行的工作将确定口腔TRM在牙周炎发病机制中的作用， 全球常见的慢性炎症性疾病（目标3）。总之，提案中概述的工作将为 一条通往我的目标的道路，即开发针对口服TRM的治疗干预措施。