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.

项目摘要/摘要 组织居民记忆T细胞（TRM）是记忆T细胞的新定义的谱系，主要位于 非淋巴组织（NLT），很少循环，是NLT的主要测量者，它们被中毒以引起 遇到重新感染后的潜在和快速反应。 TRM在鼠标和人类中很丰富，并且 我们在中枢神经系统（CNS）中进行了描述。虽然CN中的T细胞在两者中都暗示了 健康和疾病，关于大脑中TRM调节和功能的知识持续存在差距。 申请人的长期目标是了解中枢神经系统中的免疫电池功能和监视 可以针对神经旋转感染和CNS自身免疫性制定治疗策略。目的 该建议是建立对CNS中TRM功能和调节的基本理解。该建议是建立对CNS中TRM功能和调节的基本理解。 建立在抑制受体PD-1的表达的基础上，在脑TRM上是独特的，将测试 PD-1签名功能以限制TRM重新激活的幅度的假设，以防止 神经系统病理学。该假设将通过集成研究转录的技术来检验 和细胞变化以及整个动物生理学。 AIM 1将定义TRM重新激活，评估PD-1如何 信号传导调节这一点，并评估对周围免疫细胞和动物激活的影响 认识。 AIM 2将研究脑TRM重新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。经过 了解大脑TRM的调节和功能，可以建立基础知识 将TRM在病理和受保护的环境中的作用相关。申请人的病毒学博士前培训 和先天的神经免疫学，与当前的组织居民适应性免疫史的当前博士后培训融合 使她有能力解决有关神经免疫相互作用的知识的巨大差距 透视和军械库。申请人将继续与她的心理合作并利用 她当前机构的机会，以开发成功过渡到独立的必要技能 研究者。总而言之，K22职业过渡奖将使申请人能够获得她的科学和 通过提供研究和培训基础来建立一个独立的NIH资助计划，以实现职业目标 神经免疫学领域。