Function and regulation of brain resident memory T cells

大脑常驻记忆T细胞的功能和调节

• 批准号: 10350543
• 负责人: Pamela Rosato
• 金额: $ 10.7万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-12 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10350543
• 关键词: Adaptive Immune System; Address; Alzheimer' s Disease; Animals; Antibodies; Antigens; Area; Autoimmunity; Biological Response Modifiers; Biology; Blood - brain barrier anatomy; Brain; Brain Neoplasms; CNS autoimmunity; Career Transition Award; Cell physiology; Cells; Central Nervous System Diseases; Central Nervous System Infections; Cognition; Communicable Diseases; Data; Disease; Encephalitis; Environment; Equilibrium; Exposure to; Foundations; Funding; Future; Genetic Transcription; Goals; Health; Homeostasis; Human; Immune; Immune signaling; Immunity; Immunologics; Infection; Infiltration; Inflammatory; Inflammatory Response; Institution; Knowledge; Lead; Malignant Neoplasms; Mediating; Mentors; Mus; Neuraxis; Neuroimmune; Neurologic; Organ; PD-1 blockade; Pain; Pathologic; Peripheral; Physiology; Regulation; Research Personnel; Research Training; Role; Signal Transduction; Skin; Surveys; T memory cell; T-Lymphocyte; Techniques; Testing; Therapeutic; Tissues; Training; United States National Institutes of Health; Up-Regulation; Vaccine Design; Vaccines; Work; adaptive immunity; antiviral immunity; base; blood-brain barrier permeabilization; career; chemokine; combat; cytokine; cytotoxic; cytotoxicity; exhaust; experimental study; immune activation; immunopathology; improved; insight; neuroimmunology; neurotoxicity; neurotropic; pathogen; post-doctoral training; pre-doctoral; prevent; programmed cell death protein 1; programs; receptor; recruit; response; restraint; skills; vaccine platform; virology

Project Summary/Abstract Tissue resident memory T cells (TRM) are a newly define lineage of memory T cells that reside predominantly in non-lymphoid tissues (NLT), rarely recirculate and are the main surveyors of NLT where they are poised to elicit a potent and rapid response upon encountering reinfection. TRM are abundant in mouse and human and have been described in the central nervous system (CNS). While T cells in the CNS have been implicated in both health and disease, there persists a gap in knowledge regarding TRM regulation and function in the brain. The applicant’s long-term goal is to understand immune cell function and surveillance in the CNS so that improved therapeutic strategies can be developed against neurotropic infections and CNS autoimmunity. The objective of this proposal is to establish a foundational understanding of TRM function and regulation in the CNS. This proposal builds on the finding that expression of the inhibitory receptor, PD-1, is uniquely high on brain TRM and will test the hypothesis that PD-1 signlaing functions to restrain the magnitude of TRM reactivation, protecting against neurologic immunopathology. This hypothesis will be tested by integrating techniques examining transcriptional and cellular changes as well as whole animal physiology. Aim 1 will define TRM reactivation, assess how PD-1 signaling modulates this, and evaluate the impact on activation of surrounding immune cells and animal cognition. Aim 2 will investigate the impact of brain TRM reactivation on blood-brain barrier integrity, the influx of circulating immune mediators (immune cells and antibody), and how PD-1 signaling may influence this. By understanding the regulation and function of brain TRM, a foundational knowledge can be built upon to contextualize the role of TRM in pathologic and protective settings. The applicant’s pre-doctoral training in virology and innate neuroimmunology, fused with current post-doctoral training in tissue resident adaptive immunity makes her well equipped to tackle large gaps in knowledge regarding neuro-immune interactions with a unique perspective and armory of techniques. The applicant will continue to work with her mentor and take advantage of opportunities at her current institution to develop skills necessary for successful transition to an independent investigator. In summary, the K22 Career Transition Award will allow the applicant to attain her scientific and career goals by providing a base of research and training to establish an independent NIH-funded program in the field of neuroimmunology.

项目总结/摘要 组织驻留记忆T细胞（TRM）是一种新定义的记忆T细胞谱系，主要存在于组织中。 非淋巴组织（NLT），很少再循环，是NLT的主要测量者，它们准备引起 在遇到再次感染时做出有效和快速的反应。TRM在小鼠和人类中含量丰富，并且具有 在中枢神经系统（CNS）中有描述。虽然中枢神经系统中的T细胞与这两种疾病有关， 然而，在健康和疾病方面，关于TRM在大脑中的调节和功能的知识仍然存在差距。的 申请人的长期目标是了解CNS中的免疫细胞功能和监视， 可以开发针对嗜神经性感染和CNS自身免疫的治疗策略。的目标 该建议旨在建立对CNS中TRM功能和调节的基本理解。这项建议 建立在抑制性受体PD-1的表达在大脑TRM上独特地高的发现之上， 假设PD-1信号传导的功能是抑制TRM再激活的幅度， 神经免疫病理学这一假设将通过整合技术检测转录 和细胞变化以及整个动物生理学。目标1将定义TRM再激活，评估PD-1 信号传导调节这一点，并评估对周围免疫细胞和动物细胞活化的影响。 认知.目的2将研究脑TRM再激活对血脑屏障完整性的影响， 循环免疫介质（免疫细胞和抗体），以及PD-1信号传导如何影响这一点。通过 了解大脑TRM的调节和功能，可以建立基础知识， 将TRM在病理和保护环境中的作用置于背景中。申请人在病毒学方面的博士前培训 和先天神经免疫学，融合了目前的博士后培训组织居民适应性免疫 使她能够很好地解决关于神经免疫相互作用的知识的巨大空白， 透视和军械库的技术。申请人将继续与她的导师一起工作， 在她目前的机构发展必要的技能，成功过渡到一个独立的机会， 调查员总之，K22职业过渡奖将允许申请人实现她的科学和 通过提供研究和培训的基础，建立一个独立的NIH资助的项目， 神经免疫学领域