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.

项目概要/摘要 组织驻留记忆 T 细胞 (TRM) 是新定义的记忆 T 细胞谱系，主要存在于 非淋巴组织 (NLT)，很少再循环，是 NLT 的主要测量者，它们准备引发 TRM 在小鼠和人类中含量丰富，并且在遇到再感染时会产生有效且快速的反应。 已在中枢神经系统 (CNS) 中进行了描述，而 CNS 中的 T 细胞与这两种情况都有关联。 健康和疾病方面，关于大脑 TRM 调节和功能的知识仍然存在差距。 申请人的长期目标是了解中枢神经系统中的免疫细胞功能和监测，从而改善 可以针对嗜神经感染和中枢神经系统自身免疫的目标制定治疗策略。 该提案旨在建立对 CNS 中 TRM 功能和监管的基本了解。 建立在抑制性受体 PD-1 的表达在大脑 TRM 上独特高这一发现的基础上，并将测试 假设 PD-1 信号传导功能可抑制 TRM 重新激活的程度，从而防止 神经免疫病理学将通过整合转录技术进行检验。 目标 1 将定义 TRM 重新激活，评估 PD-1 的作用。 信号传导对此进行调节，并评估对周围免疫细胞和动物激活的影响 目标 2 将研究大脑 TRM 重新激活对血脑屏障完整性、血脑屏障流入的影响。 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。 了解大脑 TRM 的调节和功能，可以建立基础知识 背景化 TRM 在病理和保护环境中的作用。申请人在病毒学方面的博士前培训。 和先天神经免疫学，与当前组织驻留适应性免疫的博士后培训相融合 使她有能力利用独特的方法来解决有关神经免疫相互作用的知识上的巨大差距 申请人将继续与她的导师合作并利用。 在她目前的机构中有机会发展必要的技能，以成功过渡到独立 总之，K22 职业转型奖将使申请人获得她的科学和知识。 通过提供研究和培训基础来建立独立的 NIH 资助项目来实现职业目标 神经免疫学领域。