Function and regulation of brain resident memory T cells

项目摘要/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，主要驻留在 非淋巴组织(NLT)，很少再循环，是NLT的主要检查者，在那里它们可能会引起 在遇到再次感染时做出有力而快速的反应。TRM在小鼠和人类中含量丰富，并具有 在中枢神经系统(CNS)中已有描述。而中枢神经系统中的T细胞与这两种疾病有关 在健康和疾病方面，关于TRM的调节和大脑功能的知识差距仍然存在。这个 申请者的长期目标是了解中枢神经系统中免疫细胞的功能和监测，以便改进 可以针对神经性感染和中枢神经系统自身免疫开发治疗策略。的目标是 这项建议旨在建立对TRM在CNS中的功能和监管的基础性理解。这项建议 基于这一发现，抑制受体PD-1在大脑TRM上的表达是独一无二的，并将测试 假设PD-1信号功能抑制TRM重新激活的幅度，从而保护 神经学免疫病理学。这一假说将通过整合技术来检验转录 细胞的变化以及整个动物的生理学。目标1将定义TRM重新激活，评估PD-1如何 信号对此进行调节，并评估对周围免疫细胞和动物激活的影响 认知力。目的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信号如何影响这一点。通过 了解大脑TRM的调节和功能，可以建立在基础知识的基础上 将TRM在病理和保护环境中的作用与背景联系起来。申请人在病毒学方面的博士前训练 和先天神经免疫学，与目前的博士后组织常驻适应性免疫训练相融合 使她做好了充分的准备，可以解决关于神经免疫相互作用的知识中的巨大差距 技术的视角和武库。申请者将继续与她的导师合作，并利用 在她目前的机构发展成功过渡到独立企业所需技能的机会 调查员。总之，K22职业过渡奖将允许申请者获得她的科学和 职业目标，通过提供研究和培训基础来建立一个由美国国立卫生研究院资助的独立项目 神经免疫学领域。

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.