Dysregulation of Naïve T cell Quiescence during Aging

项目摘要/摘要 人类衰老的一个共同特征是对感染的易感性增加。这种与年龄相关的易感性是 与老年人幼稚T细胞的显著和可重复的丧失有关。值得注意的是，老化的幼稚细胞 不仅数量减少，而且还表现出部分分化的特征，意味着细胞静止状态的丧失 随着年龄的增长可能会导致曲目收缩和功能障碍。幼稚的T细胞静止状态被经典地维持 次级淋巴组织(SLT)内纤维母细胞网状细胞(FRC)。老鼠模型有典雅的 证实FRCs有能力促进T细胞存活并直接抑制活化诱导的 差异化。这些数据表明，FRC积极调节幼稚T细胞的静止，并可能发挥 在老化过程中它的损失起着至关重要的作用。然而，在人类中进行的机械学研究明显地被 很少使用单细胞技术，而且在标准的体外培养和培养中受到较差的幼稚T细胞存活率的限制 人性化的老鼠。更好地利用新的单电池技术和开发新的方法 因此，需要在体外维持幼稚T细胞，以进一步了解幼稚T细胞在 人类的衰老。我们的初步数据表明，人类幼稚T细胞具有高度的异质性，随着年龄的增长，这种细胞会变窄， 一种可以通过使用一种新的类SLT有机模型系统在体外模拟的情况。为了这个 提议，目标1将定义幼稚T细胞的总体表型、转录和表观遗传异质性 人体衰老过程中的细胞隔间。此外，AIM 2还将进一步开发类似SLT的有机化合物，用于长期- 幼稚T细胞静止的术语研究。目标3将使用我们的有机系统，结合体外和体内 体外试验，以确定FRCs在维持幼稚T细胞静止及其破坏中的作用 随着年龄的增长。这些研究的首要目标是定义基本的幼稚T细胞异质性和 确定与年龄相关的内环境平衡下降的原因-最终确定潜在的治疗干预措施 以提高老年人的保护性免疫力和预防病原性感染。申请人克莱尔博士 古斯塔夫森概述了一项综合性的五年研究和职业发展计划，以推动她 了解单细胞技术及其分析流水线，并开发一种新型的，以有机物为基础的 研究衰老过程中T细胞动态平衡的研究平台。古斯塔夫森博士的导师约尔格·戈伦齐博士 T细胞老化方面的全面专业知识以及使用High 吞吐量分析技术。这一指导与古斯塔夫森博士的专家顾问团队和 斯坦福大学提供的资源为古斯塔夫森博士提供了一个特殊的研究环境 成功成为人类免疫老化领域的一名强大的独立研究者。

Project Summary/Abstract A common feature of human aging is an increased susceptibility to infections. This age-related susceptibility is linked with a significant and reproducible loss of naïve T cells in older individuals. Notably, aged naïve cells not only reduce in number but also display features of partial differentiation, implying a loss in cellular quiescence may cause repertoire contraction and dysfunction with age. Naïve T cell quiescence is classically maintained within secondary lymphoid tissues (SLTs) by fibroblastic reticular cells (FRCs). Mouse models have elegantly demonstrated the ability of FRCs to promote T cell survival and directly inhibit activation-induced differentiation. These data suggest that FRCs actively regulate naïve T cell quiescence and likely play an essential role in its loss during aging. However, mechanistic studies in humans are significantly confounded by rare use of single cell technologies and limited by poor naïve T cell survival in standard in vitro culture and humanized mice. Better utilization of new single cell techniques and the development of novel methodologies that sustain naïve T cells in vitro is thus required to gain further insight into naïve T cell maintenance during human aging. Our preliminary data suggests high heterogeneity of human naïve T cells that narrows with age, a situation that can be mimicked in vitro through the use of a novel SLT-like organoid model system. For this proposal, Aim 1 will define the overall phenotypic, transcriptional and epigenetic heterogeneity of the naïve T cell compartment during human aging. In addition, Aim 2 will further develop SLT-like organoids for the long- term study of naïve T cell quiescence. Aim 3 will use our organoid system, in combination with ex vivo and in vitro assays, to determine the role of FRCs in the maintenance of naïve T cell quiescence and its breakdown with aging. The overarching goals of these studies are to define fundamental naïve T cell heterogeneity and determine causes of age-related homeostatic decline – to ultimately identify potential therapeutic interventions to boost protective immunity and prevent pathogenic infections in older individuals. The applicant Dr. Claire Gustafson has outlined an integrative five-year research and career development plan to advance her knowledge in single cell techniques and their analysis pipelines and to develop a novel, organoid-based research platform to study T cell homeostasis during aging. Dr. Gustafson’s mentor, Dr. Jörg Goronzy, has comprehensive expertise in T cell aging as well as an extensive network of scientific collaborators using high throughput analytical techniques. This mentorship combined with Dr. Gustafson’s team of expert advisors and the resources available at Stanford University provides an exceptional research environment for Dr. Gustafson to successfully become a strong independent investigator in the area of human immune aging.