T cells in the aging brain

衰老大脑中的 T 细胞

• 批准号: 10184422
• 负责人: ANNE BRUNET
• 金额: $ 75.22万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-15 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10184422
• 关键词: Address; Adult; Affect; Age; Aging; Alzheimer' s Disease; Animals; Antigens; Biological Assay; Blood; Brain; Brain region; Cells; Clonal Expansion; Clone Cells; Coculture Techniques; Cytotoxic T-Lymphocytes; Data; Deterioration; Disease; Elderly; Endothelial Cells; Environmental Risk Factor; Evaluation; Exercise; Exhibits; Goals; Human; Immune; Immune checkpoint inhibitor; Immunofluorescence Immunologic; Immunotherapy; Impairment; In Vitro; Individual; Infiltration; Interferons; Knowledge; Learning; Libraries; Location; Machine Learning; Memory; Microglia; Modeling; Mus; Natural regeneration; Nervous system structure; Neurodegenerative Disorders; Neurons; Neurophysiology - biologic function; Organ; Organism; Play; Prevalence; Production; Rejuvenation; Role; Signal Transduction; T cell receptor repertoire sequencing; T cell regulation; T-Cell Depletion; T-Lymphocyte; Testing; Tissues; Tumor-infiltrating immune cells; Work; age related; age related neurodegeneration; aging brain; base; cell type; cognitive enhancement; cognitive function; cytokine; cytotoxic; cytotoxicity; exhaustion; experimental study; functional decline; functional restoration; immunoregulation; improved; in vivo; in vivo evaluation; insight; middle age; nerve stem cell; neuroblast; neurogenesis; normal aging; preservation; prevent; regenerative; response; restoration; single-cell RNA sequencing; stem cell proliferation; subventricular zone; transcriptome

SUMMARY The overarching goal of this project is to understand how immune cells impact the brain during aging, with the objective of restoring old brain function. The brain has long been considered an ‘immuno-privileged organ’. However, recent studies have shown that immune cells infiltrate the brain in neurodegenerative diseases such as Alzheimer’s disease and during aging. A key remaining challenge is to understand how immune cells impact the brain during aging, and could this knowledge be used to restore functionality of old brain and treat neurodegenerative diseases? The subventricular zone (SVZ) of the adult brain provides a great paradigm to address this question, as this regenerative region of the brain contains many different cell types – neural stem cells (NSCs), endothelial cells, microglia – and exhibits clear functional decline during aging. To gain a single cell understanding of the changes that occur with age in neurogenic niches, we recently performed single cell RNA-sequencing of young and old neurogenic niches in mice. This analysis revealed a striking infiltration of cytotoxic T cells only in the old neurogenic niche, which was confirmed by immunofluorescence. Surprisingly, we found that T cells from old SVZs are clonally expanded and secrete interferon g (IFNg), suggesting that they have encountered specific antigens. We also showed that T cells can impair NSC proliferation both in co-cultures and in vivo. Based on these data, our specific hypothesis is that T cell clonal expansion in old brains drives the deterioration of the neurogenic niche with age, and that preventing this T cell expansion restores function to old neurogenic regions. Probing this idea would be critical to counter the decline in brain function during aging and neurodegenerative diseases, such as Alzheimer’s disease. To test our hypothesis, we propose the following experiments: 1. To determine how T cells infiltrate neurogenic niches in old individuals; 2. To understand the functional impact of T cells on old neurogenic niches; 3. To examine the interaction between immune cells and neurogenic niches in young, old, and rejuvenated individuals. Completion of these aims will provide unique mechanistic insights into the regulation of T cell and other immune cells during aging in regenerative niches of the brain. This work should also give a fundamental understanding of the mechanistic impact of the interferon response and T cell cytotoxicity on different cell types in the brain. Knowledge from our study should pave the way for building transformative strategies, including new immunotherapies, for the restoration of a pristine tissue, which will be a critical step for improving brain function during aging and age-related diseases such as Alzheimer’s disease.

概括 该项目的总体目标是了解免疫细胞在衰老过程中如何影响大脑， 恢复旧大脑功能的目标。长期以来，大脑一直被认为是“免疫特权器官”。 然而，最近的研究表明，在神经退行性疾病（如神经退行性疾病）中，免疫细胞会渗入大脑。 如阿尔茨海默病和衰老过程中。剩下的一个关键挑战是了解免疫细胞如何影响 大脑在衰老过程中的作用，这些知识是否可以用来恢复老大脑的功能并治疗 神经退行性疾病？ 成人大脑的室下区（SVZ）为解决这个问题提供了一个很好的范例，因为 大脑的再生区域包含许多不同的细胞类型——神经干细胞（NSC）、内皮细胞、 小胶质细胞——并在衰老过程中表现出明显的功能衰退。获得对变化的单细胞理解 神经源性生态位中随着年龄的增长而发生的情况，我们最近对年轻人和老年人进行了单细胞 RNA 测序 小鼠的神经源性生态位。该分析揭示了细胞毒性 T 细胞仅在旧细胞中出现惊人的浸润。 神经源性生态位，通过免疫荧光证实。令人惊讶的是，我们发现来自老年的 T 细胞 SVZ 克隆扩增并分泌干扰素 g (IFNg)，表明它们遇到了特定的 抗原。我们还表明，T 细胞可以在共培养物和体内损害 NSC 增殖。基于 根据这些数据，我们的具体假设是，老年大脑中的 T 细胞克隆扩张导致了大脑功能的恶化。 随着年龄的增长，神经源性生态位，并且阻止这种 T 细胞扩张可以恢复旧神经源性区域的功能。 探索这一想法对于应对衰老和神经退行性疾病期间大脑功能的下降至关重要 疾病，例如阿尔茨海默病。为了检验我们的假设，我们提出以下实验： 1. 确定T细胞如何浸润老年个体的神经源性微环境； 2.了解T细胞对旧神经源性微环境的功能影响； 3. 研究年轻、年老和恢复活力的免疫细胞与神经源性微环境之间的相互作用 个人。 这些目标的完成将为 T 细胞和其他细胞的调节提供独特的机制见解。 衰老过程中大脑再生生态位中的免疫细胞。这项工作还应该提供一个基本的 了解干扰素反应和 T 细胞细胞毒性对不同细胞类型的机械影响 在大脑中。我们研究中的知识应该为制定变革战略铺平道路，包括 新的免疫疗法，用于恢复原始组织，这将是改善大脑的关键一步 在衰老和与年龄相关的疾病（如阿尔茨海默氏病）过程中发挥作用。