Regulation and Function of Oral Resident Memory T Cells

口腔驻留记忆 T 细胞的调节和功能

基本信息

批准号：
10436381
负责人：
James Michael Stolley
金额：
$ 10.64万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10436381
关键词：
Address Allergic Allergic Disease Animal Model Antibiotics Antibodies Antigens Aphthous Stomatitis Architecture Autoantigens Autoimmune Autoimmune Diseases Autoimmunity Bacteria Biology Blood CD8-Positive T-Lymphocytes CD8B1 gene Cells Chemicals Chronic 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 Inflammation Inflammatory Intercept Invaded Knockout Mice Knowledge Ligature Location Lung Maintenance Malignant Neoplasms Mediating Mediator of activation protein 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 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 base 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 translational potential tumor urogenital tract

Address Allergic Allergic Disease Animal Model Antibiotics Antibodies Antigens Aphthous Stomatitis Architecture Autoantigens Autoimmune Autoimmune Diseases Autoimmunity Bacteria Biology Blood CD8-Positive T-Lymphocytes CD8B1 gene Cells Chemicals Chronic 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 Inflammation Inflammatory Intercept Invaded Knockout Mice Knowledge Ligature Location Lung Maintenance Malignant Neoplasms Mediating Mediator of activation protein 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 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 base 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 translational potential tumor urogenital tract

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项目摘要

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.

项目摘要/摘要记忆T细胞记录了一个人的传染性过去和负担得起的保护以重新感染。历史上定义在血液中，根据它们获得次级淋巴器官的能力，并细分最近描述了T细胞免疫监视的。在这里，内存T单元格忘记了全身性再循环以换取在非淋巴组织（NLT）中持久居住。这样的组织居住记忆t 细胞（TRM）提供了一种通常被利用的特定屏障舱内储存免疫力的机制通过病原体作为进入体内的门户。 TRM功能通过迅速拦截入侵的病原体和编排协作免疫调查。在NLT内，T细胞免疫监视占主导地位在加速防止再感染的地方，可能与肿瘤控制有关，并且也可能促进某些过敏和自身免疫性疾病的持久性。这些观察结果支持了TRM 作为疫苗接种的主要目标。 TRM的治疗操作对治疗有很大的希望有机特异性免疫疾病，自身免疫性和固体癌症。而在其他方面进行了广泛研究粘膜部位，目前在我们对个体发育，功能和口腔粘膜TRM的治疗意义。在建筑和生物学上最多样化的视为中。体内的组织部位，嘴巴不断受到无数饮食和环境抗原的轰炸拥有潜水微生物社区。此外，口腔和唾液网格可以被细菌殖民，真菌和病毒病原体，包括单纯疱疹病毒和人乳头状瘤病毒。鉴于他们的良好在其他NLT中介导屏障免疫监视方面的记录和关键功能，口服TRM可能会在抗病毒免疫史和口服免疫史的免疫史免疫史免疫史中发挥重要作用在牙周疾病和口腔地衣平面中观察到的反应。但是，解决他们在这些中的作用临床上相关的环境缺乏动物模型，这将有助于产生足够的口服TRM来操纵和学习。我通过开发小说的口头“ Prime-Pull”来弥合这一差距策略是同类策略，用于在口腔粘膜中产生大量可牵引的TRM。利用这个创新的方法，我将解决有关口服TRM生物学的杰出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服TRM的信号对耗尽致病子集的影响（AIM 1）。实验跨越 K99/R00阶段将研究口服TRM重新激活在塑造微生物和口腔的炎症景观与重新口腔感染和口腔癌具有临床相关性（AIM 2）。在R00阶段进行的工作将定义口服TRM在牙周炎发病机理中的作用，这是最多的全球常见的慢性炎症状况（AIM 3）。总而言之，该提案中概述的工作将铺路朝着我制定针对口服TRM的治疗干预措施的目标的前进道路。