Regulation and Function of Oral Resident Memory T Cells

项目摘要/摘要 记忆T细胞记录个人感染的过去，并为再次感染提供保护。历史上定义的 在血液中，并根据其访问次级淋巴器官的能力进行细分，这是一种额外的机制 T细胞免疫监视的作用最近被描述出来。在这里，记忆T细胞放弃了系统性 再循环以换取在非淋巴组织中的持久停留(NLT)。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内储存免疫的机制 通过病原体作为进入人体的门户。TRM通过快速拦截入侵病原体和 协调协作免疫反应。在NLT中，T细胞免疫监视以TRM为主 它们加速了对再感染的保护，可能与肿瘤控制有关，也可能 促进某些过敏性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。在其他地方广泛研究的同时 粘膜部位，目前我们对其个体发生、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 身体中的组织部位，口腔不断受到无数饮食和环境抗原的轰炸， 拥有不同的微生物群落。此外，口腔和唾液腺可能会被细菌侵占， 真菌和病毒病原体，包括单纯疱疹病毒和人乳头瘤病毒。鉴于他们的健康状况- 在其他NLT，口服TRM在介导屏障免疫监测中的记录和关键功能可能 在抗病毒免疫和口服免疫动态平衡中发挥重要作用。TRM还可能使慢性免疫持续存在 牙周病和口腔扁平苔藓的疗效观察。然而，解决他们在这些方面的角色 临床上相关的环境由于缺乏动物模型而受到影响，这些动物模型将有助于产生 足够的口腔TRM进行操作和学习。我已经通过开发一种新颖的口头‘质拉法’来弥合这一差距 这是第一个在口腔粘膜中产生大量易处理的TRM的策略。利用这一点 创新的方法，我将解决关于口腔TRM生物学的悬而未决的基本问题 人类口腔健康的翻译潜力。在K99阶段，我将定义招聘和保留 管理口服TRM的信号及其对耗尽致病亚群的影响(目标1)。横跨世界各地的实验 K99/R00阶段将研究口服TRM重新激活在塑造微生物和 口腔炎症景观与复发性口腔感染和口腔癌的临床相关性(目的 2)。在R00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，最 全球常见慢性炎症性疾病(目标3)。总之，提案中概述的工作将为 朝着我的目标前进的道路，即开发针对口腔TRM的治疗干预措施。

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.