Dysregulation of Naïve T cell Quiescence during Aging

衰老过程中幼稚 T 细胞静止的失调

基本信息

批准号：
10661554
负责人：
Claire Gustafson
金额：
$ 12.63万
依托单位：
ALLEN INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-26 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10661554
关键词：
ATAC-seq Acceleration Adenosine Age Aging Antigens Area Biological Assay Biological Models Biomedical Engineering Cell Aging Cell Compartmentation Cell Differentiation process Cell Maintenance Cell Survival Cell physiology Cells Cellular Indexing of Transcriptomes and Epitopes by Sequencing Cellular biology Cytometry Data Data Set Development Development Plans Encapsulated Environment Epigenetic Process Flow Cytometry Functional disorder Genetic Transcription Goals Heterogeneity Homeostasis Human IL7 gene Immune Immune response Immunity In Vitro Incidence Individual Infection Intervention Knowledge Light Link Longitudinal Studies Lymphoid Lymphoid Tissue Maintenance Mediating Mediator Memory Mentors Mentorship Methodology Organoids Pathogenicity Pathway interactions Phenotype Play Population Population Heterogeneity Predisposition Production Property Prostaglandins RNA Reproducibility Research Research Personnel Resources Reticular Cell Role Signal Transduction Stromal Cells System T-Lymphocyte Techniques Therapeutic Intervention Time Tissues Universities Work age related aged analysis pipeline career development cytokine functional loss healthspan humanized mouse immune function improved in vitro Assay innovation insight middle age mortality mouse model novel peripheral blood prevent research and development single cell technology stem

项目摘要

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.

项目摘要/摘要人衰老的一个共同特征是增加对感染的敏感性。与年龄有关的易感性是与老年人的幼稚T细胞的显着且可重复的损失有关。值得注意的是，老年细胞不是仅减少数量，但还显示部分分化的特征，这意味着细胞静止的损失可能会导致曲目收缩和年龄功能障碍。幼稚的T细胞静止是经典维持的成纤维细胞网细胞（FRC）内次要淋巴组织（SLT）。鼠标模型优雅证明了FRC促进T细胞存活并直接抑制激活诱导的能力分化。这些数据表明，FRC会主动调节幼稚的T细胞静止，并可能发挥在衰老期间损失中的重要作用。但是，人类的机械研究被显着混淆在标准体外培养和人源化的小鼠。更好地利用新的单细胞技术和新方法的发展因此，需要在体外维持幼稚的T细胞，以进一步深入了解幼稚的T细胞在维持过程中的维持人类衰老。我们的初步数据表明，随着年龄的增长，人类天真T细胞的高异质性，可以通过使用新型SLT样的类器官模型系统在体外模仿的情况。为了这提案，AIM 1将定义幼稚T的整体表型，转录和表观遗传异质性人衰老期间的细胞室。此外，AIM 2将进一步发展为长期的SLT样手奏幼稚T细胞静止的术语研究。 AIM 3将使用我们的类器官系统，并结合前体和IN 体外测定，确定FRC在维持幼稚T细胞静止及其分解中的作用随着衰老。这些研究的总体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稳态下降的原因 - 最终确定潜在的治疗干预措施提高保护性免疫学并防止老年人的致病感染。申请人克莱尔博士古斯塔夫森（Gustafson）概述了一项综合研究和职业发展计划，以推动她单细胞技术及其分析管道的知识，并开发基于器官的新型，基于器官的知识研究在衰老期间研究T细胞稳态的研究平台。 Gustafson博士的精神，JörgGoronzy博士， T细胞衰老方面的全面专业知识以及使用高的科学合作者网络吞吐量分析技术。这种精明制度结合了古斯塔夫森博士的专家顾问团队，斯坦福大学可用的资源为古斯塔夫森博士提供了卓越的研究环境成功成为人类免疫衰老领域的强大独立研究者。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Understanding T cell aging to improve anti-viral immunity.

DOI：
10.1016/j.coviro.2021.09.017
发表时间：
2021-12
期刊：
Current opinion in virology
影响因子：
5.9
作者：
Zhang H;Weyand CM;Goronzy JJ;Gustafson CE
通讯作者：
Gustafson CE

Association of Premature Immune Aging and Cytomegalovirus After Solid Organ Transplant.

DOI：
10.3389/fimmu.2021.661551
发表时间：
2021
期刊：
Frontiers in immunology
影响因子：
7.3
作者：
Higdon LE;Gustafson CE;Ji X;Sahoo MK;Pinsky BA;Margulies KB;Maecker HT;Goronzy J;Maltzman JS
通讯作者：
Maltzman JS

Naïve T Cell Quiescence in Immune Aging.

免疫衰老中的幼稚 T 细胞静止。