T cells in the aging brain

摘要 这个项目的首要目标是了解免疫细胞在衰老过程中如何影响大脑， 目的是恢复陈旧的脑功能。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，在神经退行性疾病中，免疫细胞渗透到大脑中 作为阿尔茨海默氏症和在衰老期间。剩下的一个关键挑战是了解免疫细胞如何影响 衰老过程中的大脑，这一知识能否用于恢复衰老大脑的功能和治疗 神经退行性疾病？ 成人大脑的脑室下区(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类型的细胞--神经干细胞(NSCs)，内皮细胞， 小胶质细胞--在衰老过程中表现出明显的功能衰退。为了让单个细胞了解这些变化 我们最近对年轻人和老年人进行了单细胞rna测序。 小鼠的神经性小生境。这项分析显示，只有在老年人中才有显著的细胞毒性T细胞的渗透 神经源性生态位，免疫荧光证实。令人惊讶的是，我们发现古老的T细胞 SVZ克隆扩增并分泌干扰素g(IFNG)，这表明它们遇到了特定的 抗原。我们还发现，在共培养和体内培养中，T细胞都可以损害NSC的增殖。基于 这些数据，我们的特定假设是，T细胞在老年大脑中的克隆性扩张导致了 随着年龄的增长，神经源性的生态位，阻止这种T细胞的扩张，将功能恢复到旧的神经源性区域。 探索这一观点对于对抗衰老和神经退行性变过程中大脑功能的下降至关重要 疾病，如阿尔茨海默氏症。为了验证我们的假设，我们提出了以下实验： 1.确定T细胞如何渗入老年人的神经源性壁龛； 2.了解T细胞对陈旧的神经源性生态位的功能影响； 3.研究免疫细胞与神经源性生态位之间的相互作用 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械性见解 老化过程中大脑再生壁龛中的免疫细胞。这项工作也应该给出一个基本的 了解干扰素应答和T细胞杀伤对不同细胞类型的机制影响 在大脑里。我们研究的知识应该为建立变革性战略铺平道路，包括 新的免疫疗法，恢复原始组织，这将是改善大脑的关键一步 在衰老和阿尔茨海默氏症等与年龄相关的疾病中发挥作用。

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.